Endogenous Vasoactive Peptides and Vascular Aging-Related Diseases

Chen, Yao; Qi, Yongfen; Lu, Weiwei

doi:https://doi.org/10.1155/2022/1534470

Oxidative Medicine and Cellular Longevity

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Review Article | Open Access

Volume 2022 | Article ID 1534470 | https://doi.org/10.1155/2022/1534470

Endogenous Vasoactive Peptides and Vascular Aging-Related Diseases

Yao Chen,¹Yongfen Qi,²and Weiwei Lu³

Academic Editor: Silvana Hrelia

Received04 Apr 2022

Revised26 Aug 2022

Accepted15 Sept 2022

Published03 Oct 2022

Abstract

Vascular aging is a specific type of organic aging that plays a central role in the morbidity and mortality of cardiovascular and cerebrovascular diseases among the elderly. It is essential to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes. Endogenous vasoactive peptides are compounds formed by a group of amino acids connected by peptide chains that exert regulatory roles in intercellular interactions involved in a variety of biological and pathological processes. Emerging evidence suggests that a variety of vasoactive peptides play important roles in the occurrence and development of vascular aging and related diseases such as atherosclerosis, hypertension, vascular calcification, abdominal aortic aneurysms, and stroke. This review will summarize the cumulative roles and mechanisms of several important endogenous vasoactive peptides in vascular aging and vascular aging-related diseases. In addition, we also aim to explore the promising diagnostic function as biomarkers and the potential therapeutic application of endogenous vasoactive peptides in vascular aging-related diseases.

1. Introduction

Cardiovascular and cerebrovascular diseases are the most common causes of death among the elderly [1]. Many of these age-related vascular diseases, such as atherosclerosis, hypertension, vascular calcification, abdominal aortic aneurysms (AAAs), Alzheimer’s disease, cerebral small vessel disease, and stroke, are mainly due to vascular aging [2, 3]. Thus, vascular aging is recently regarded as a critical factor in the prevalence and mortality of vascular disorders in older people. Effective interventions to combat vascular aging are urgent for the prevention of age-related vascular diseases.

A large body of evidence documents that some endogenous vasoactive peptides serve as novel intercellular information communicators between cells, which are associated with most of aging-related disorders [4, 5]. Vasoactive peptides are produced in neurons, heart, blood vessels, and other tissues, and they help maintain vascular homeostasis and mediate the pathogenesis of cardiovascular diseases (CVDs) mainly by regulating the functions of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) via their receptors. They have many advantages, including small molecular weight, simple structure, wide tissue distribution, diverse biological effects, rapid synthesis and metabolism, and low immunogenicity [4–6]. Recently, vasoactive peptides have attracted attention because of their value in the diagnosis and treatment of some CVDs. For example, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs) are primarily designed to block and/or reduce the detrimental effects of angiotensin II (Ang II); and brain natriuretic peptide (BNP) and N-terminal proBNP (NT proBNP) are used as nonspecific biomarkers for the diagnosis of heart failure. Therefore, vasoactive peptides might be a potential biomarker for diagnosis and therapeutic target in treating vascular aging-related diseases. Here, we summarize the current knowledge on the roles of some common vasoactive peptides in vascular aging and age-related vascular pathologies, as well as the diagnostic use and therapeutic application of these peptides (Figure 1).

Figure 1

Vascular aging and related diseases. The mechanisms of vascular aging include oxidative stress, inflammation, mitochondrial dysfunction, telomere shortening, DNA damage, upregulation of SASP factors, NAD⁺ depletion, and progerin accumulation. Vascular aging is a pivotal risk factor promoting the development and progression of vascular aging-related diseases, such as atherosclerosis, hypertension, vascular calcification, abdominal aortic aneurysms, Alzheimer’s disease, and stroke. Abbreviations: SASP: senescence-associated secretory phenotype.

CVDs and cerebrovascular diseases are the major cause of death globally [7]. Aging is one of the main risk factors for multiple vascular disorders, including CVDs and cerebrovascular diseases, resulting in a progressive structural and functional decline of the vascular networks [3, 7]. Today, the aging population is growing dramatically, and the number of adults over 65 is projected to increase from 617.1 million to 1 billion by 2030 and to 1.6 billion by 2050 [8]. Many age-related vascular diseases are due to the aging-induced functional and phenotypic alterations of the microcirculation [2]. Accumulating evidence indicated that vascular aging is a major trigger of many vascular disorders and enhances the incidence and mortality of atherosclerosis [9], hypertension [10], cerebral small vessel disease [11], Alzheimer’s disease [12], stroke [11], etc.

Vascular aging is a specific type of organic aging characterized by structural and functional alterations in the vasculature, including vascular cell senescence, extracellular matrix (ECM) remodeling, oxidative stress, inflammation, apoptosis, and calcification, which are implicated in the development and progression of vascular aging-related diseases [13]. Vascular aging and vascular diseases interact with each other. The aging vasculature provides a microenvironment for the onset and development of vascular diseases, while vascular diseases accelerate the process of vascular aging. The mechanisms involved in the pathogenesis of vascular aging include oxidative stress, mitochondrial dysfunction, inflammation, premature cellular senescence, DNA damage, maladaptation to molecular stresses, impaired maintenance of proteostasis, deregulated nutrient sensing, stem cell dysfunction in the vascular system, and impairments in the synthesis and secretion of vasoactive molecules [2, 14–16]. These molecular and physiological alterations lead to the stiffening and thickening of the vessel wall, as well as endothelial dysfunction and vascular tone dysregulation [15, 17]. ECs and VSMCs are the two primary major cell types within the vasculature, and their structural and functional disruptions are the major causes of vascular aging, which could influence the onset, process, and severity of age-related vascular diseases [2, 18]. Therefore, improving functional disorders of ECs and VSMCs by targeting fundamental cellular and molecular aging processes might ameliorate vascular aging, providing potential therapeutic strategies to prevent/delay vascular aging-related diseases (Figure 1).

Aging occurs progressively in both men and women, however, the progress of vascular aging in women appears to be slowed, as compared to men, and accelerated during the menopause transition. The reasons for these sex differences in vascular aging are not completely understood but may be related to gonadal aging and the changes of sex hormones during aging [19]. Previously, the regulatory influence of sex hormones on vascular aging was attributed to the effects of menopause and declines in estradiol in women. Increasing data suggest that decreasing testosterone levels in men contribute to accelerated vascular aging [19, 20]. To date, the effects of testosterone in women remain ambiguous. Although the androgen levels in healthy women across the lifespan show wide variations, all androgens and androgenic prohormones including testosterone, seem to decrease with age [21]. Mineralocorticoid receptors in smooth muscle cells may contribute to vascular aging in both sexes but by different mechanisms [22].

Since vascular aging is the basis of a variety of vascular diseases, better understanding of the mechanism, early detection, and intervention of vascular aging will provide a new direction of diagnosis, treatment, and prognosis of vascular aging-related diseases, especially in cardiovascular and cerebrovascular diseases. Additionally, sex-specific therapeutic strategies are also necessary for the prevention of vascular aging-related diseases.

3.1. Angiotensin 1-7 (Ang-(1-7))

Ang-(1-7), a biologically active peptide in the renin-angiotensin system (RAS) family, is converted from Ang I, Ang II, or Ang-(1-9) by neprilysin (NEP), ACE2, vascular endothelium prolyl endopeptidase, or smooth muscle thimet oligopeptidase [23]. By virtue of its actions on the G protein-coupled receptor Mas, Ang-(1-7) opposes the cardiovascular deleterious effects of Ang II, one of the most abundant components of RAS. Recent preclinical translational studies indicate a critical counterregulatory role of the ACE2/Ang-(1-7) axis on the activated RAS and other non-RAS stressors involved in many aging-related diseases.

RAS plays a central role in regulating extracellular fluid volume, vascular biology, normal blood vessel function, and pathogenesis of CVDs [23]. In the RAS, angiotensinogen is transformed by renin into Ang-I, which is then mainly cleaved into the potent vasoconstrictor, Ang-II via ACE. Ang II, the main vasoactive peptide in the systemic RAS, causes vasoconstriction and salt and water retention, induces cardiac and vascular remodeling, and promotes the detrimental effects of other neurohormonal systems, mainly via the Ang II type 1 receptor (AT1R), which is widely expressed in the cardiovascular system [24]. By binding to the Ang II type 2 receptor (AT2R), Ang II can also mediate vasodilatory effects. ACE inhibitors, ARBs, and inhibitors that target other vasopeptidases as well as receptors for vasoactive peptides are primarily designed to attenuate the adverse pathophysiological effects of Ang II for treatment of a wide range of indications related to CVDs and renal diseases [25]. These inhibitors of RAS have showed favourable long-term effects in experimental and clinical CVDs [4]. Increasing evidence demonstrated that upregulation of tissue RAS participates in the pathogenesis of vascular aging promoting intimal thickening and vascular remodeling in aged animals and old people [26, 27]. Furthermore, pharmacological inhibition of RAS activity can attenuate the stiffness of vasculature in aged animals and elderly humans independently of decreasing blood pressure [28, 29]. Recently an extended renin-angiotensin-aldosterone system, as well as the local RAS in the vasculature play a tissue-specific role in modulation of aging processes [25].

Ang (1-7) plays a counterregulatory role to ACE/Ang II/AT1R axis, eliciting a range of effects such as vasodilatation, inhibition of VSMC proliferation, and protection against oxidative stress and inflammation [24]. In vitro, Ang-(1-7) exerted protective effects against human EC senescence by consecutively activating klotho and the cytoprotective nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway through the Mas receptor [30]. Similarly, Ang-(1-7) also mitigated the senescence of VSMCs by inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nuclear factor kappa-B (NF-κB) induced by Ang II [31].

Ang-(1-7) acts as a potent vasodilator in multiple vascular beds. In spontaneously hypertensive rats (SHRs), Ang-(1-7) caused dose-dependent relaxation in the artery by activating the NO-cyclic guanosine monophosphate- (cGMP-) dependent protein kinase G (PKG) pathway via the Mas receptor [32]. In addition, Ang-(1-7) could decrease the Ang II-induced contractile response in rat aortas by inhibiting extracellular regulated protein kinase (ERK) 1/2 activation via regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1) activity [33]. In aged male rats, the vasodepressor effect of Ang-(1-7) was mediated via stimulation of both AT2R and Mas receptor compared to exclusive stimulation of AT2R in adult male rats [34]. However, in old female mice, the Ang-(1-7)-mediated vasodilatory effect was absent but could be restored by estradiol replacement. Thus, the vasodilatory effect of Ang-(1-7) could be affected by estradiol changes during aging [35]. Current research has shown that Ang-(1-7) attenuated the development of atherosclerosis [36] and increased the stability of atherosclerotic plaques [37] through activation of the Mas receptor [36]. Likewise, Ang-(1-7)-treated AAA mice showed decreased vascular inflammation, ECM degradation, and VSMC apoptosis, and its effects were mediated by inhibition of ERK1/2 signaling pathway via both Mas and AT2R [38].

Evidence from clinical studies points to a possible interaction between Ang-(1-7) and vascular lesions. Ang-(1-7) levels in plasma were significantly lower in the Alzheimer’s disease patients. The compensatory circulating Ang-(1-7) might protect against Alzheimer’s disease-related damages by increasing cerebral blood flow, reducing blood-brain barrier (BBB) permeability, and inhibiting inflammation [39]. Durand et al. [40] have shown that Ang-(1-7) restored physiological nitric oxide- (NO-) mediated vasodilation of atrial and adipose arterioles in humans with coronary artery disease. In particular, the protective actions of Ang-(1-7) on the human endothelium seem to occur via increased transcriptional activation of TERT, the catalytic subunit of telomerase [40]. However, when administered intravenously, Ang-(1-7) has a short bioavailability for its rapid degradation by circulating enzymes. Several stabilized forms are currently under investigation, including cyclic Ang-(1-7), cyclodextrins-included or bioencapsulated Ang-(1-7), and Ang-1-6-O-Ser-Glc-NH2 (PNA5) [41]. More clinical pharmacological strategies need to be explored in the future (Figure 2).

Figure 2

The mechanisms of Ang-(1-7) in protecting against vascular damage. Most cardiovascular effects of Ang-(1-7) are likely to be mediated by the Mas receptor. However, Ang-(1-7) also has a weak affinity for AT2R. By binding to its receptors, Ang-(1-7) exerts a wide range of effects on blood vessels, such as antisenescence, anti-inflammatory, antiapoptotic, and vasodilative effects. Abbreviations: Ang-(1-7): angiotensin-(1-7); AT2R: angiotensin type 2 receptor; cGMP: cyclic guanosine monophosphate; EC: endothelial cell; ERK: extracellular regulated protein kinases; eNOS: endogenous nitric oxide synthase; HO-1: heme oxygenase-1; MKP-1: mitogen-activated protein kinase phosphatase-1; NADPH: nicotinamide adenine dinucleotide phosphate; NF-κB: nuclear factor kappa-B; NO: nitric oxide; Nrf2: nuclear factor-erythroid 2-related factor 2; PKG: protein kinase G; VSMC: vascular smooth muscle cell.

3.2. Apelin

Apelin, first discovered in 1998, is an endogenous ligand for the G protein-coupled receptor APJ [42]. The apelin-APJ signal transduction pathway is widely expressed throughout the cardiovascular system. Preproapelin, a 77-amino acid, is sequentially decomposed by ACE into several shorter C-terminal bioactive peptides, including apelin-12, apelin-13, apelin-17, and apelin-36 [43, 44]. Apelin-13 is the most potent peptide that has the primary active biological function [43]. A large number of studies indicate that apelin/APJ is involved in the regulation of renin-angiotensin-aldosterone system activity [45, 46], oxidative stress [47, 48], inflammation [49, 50], autophagy, apoptosis [51–53], and activation of stem cells [54] during the development of aging.

Studies showed that apelin-12 and apelin-13 attenuated vascular cell senescence by various pathways in vitro. Apelin-13/APJ axis improved Ang II-induced HUVEC senescence, which in turn improved cellular viability. These cellular protections were associated with reduced reactive oxygen species (ROS) production and enhanced telomerase activity via the AMP-activated protein kinase (AMPK)/sirtuin1 (SIRT1) signaling [45]. Likewise, apelin-13 effectively attenuated calcification by suppressing ROS-mediated DNA damage and improving the dysfunction of MAPKs and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) in high glucose-treated VSMCs [55]. In high glucose-treated microvascular ECs, the level of apelin-12 was markedly decreased, whereas exogenous apelin-12 treatment suppressed inflammation and oxidative stress by inhibiting C-jun kinase enzyme (JNK) and p38 mitogen-activated protein kinase (MAPK) pathway [56].

Apelin and APJ receptor expression were downregulated with age in mice, and that deficiency of apelin accelerated cardiovascular aging, whereas its restoration extended the mice healthspan [57]. ACE2 is an important target of apelin action in the vasculature. Loss of apelin caused age-dependent heart dysfunction, which was associated with decreased ACE2 levels [58]. Also, apelin knockout (KO) potentiated Ang II-induced AAA formation in mice, due to the lack of apelin-mediated upregulation of ACE2 and its prosurvival effects on VSMCs [59]. Moreover, NEP is a major enzyme that metabolizes and inactivates apelin. The researchers further found treatment with a stable apelin-17 analog, which is resistant to NEP cleavage, ameliorated Ang II-mediated AAA formation [59]. Intravenous pretreatment of rats with apelin-17 also markedly reduced cerebral infarct volume after middle cerebral artery occlusion (MCAO) [60]. In addition, in rats with vascular calcification, apelin-13 significantly ameliorated aortic calcification by preventing endoplasmic reticulum stress (ERS) through activation of Akt signaling [61].

In recent years, there has been growing clinical evidence of apelin’s involvement in the pathogenesis of vascular aging-related diseases. A human study has demonstrated decreased plasma apelin concentrations and impaired NO bioavailability in older hypertensive patients, while high-intensity interval training reduced blood pressure by increasing apelin and nitrite/nitrate (NOx) plasma levels. Interestingly, the elevation of plasma apelin level was associated with a concomitant elevation of plasma NOx level [62]. Meanwhile, ischemic stroke patients with good collateral circulation had significantly higher plasma apelin-17 and apelin-36 levels than patients with poor collateral circulation [60]. Moreover, direct administration of the pyroglutamated form of apelin-13 has been shown to significantly increase cardiac index and lowered mean arterial pressure and peripheral vascular resistance in healthy control subjects as well as in patients with heart failure [63, 64]. However, the short half-life of apelin greatly limits its therapeutic utility for patients. Potent and safe small molecule activators of APJ need to be developed (Figure 3).

Figure 3

The protective effects of apelin-13 on vascular cell senescence. By binding to APJ, apelin-13 inhibits EC senescence and VSMC calcification via AMPK/SIRT1, MAPK, and PI3K/Akt pathways. Abbreviations: Akt: protein kinase B; AMPK: AMP-activated protein kinase; APJ: apelin receptor; EC: endothelial cell; ERS: endoplasmic reticulum stress; MAPK: mitogen-activated protein kinase; PI3K: phosphatidylinositol 3 kinase; ROS: reactive oxygen species; SIRT1: sirtuin1; VSMC: vascular smooth muscle cell.

3.3. Calcitonin Gene-Related Peptide (CGRP) Family

CGRP family peptides, including calcitonin, CGRP, adrenomedullin (AM), intermedin (IMD), and amylin, have been identified from various vertebrates and have a range of biological activities. Accumulating evidence has suggested the protective roles of CGRP, AM, and IMD in aging-related vascular diseases. These peptides exert effects by binding to calcitonin receptor-like receptor (CRLR)/receptor activity-modifying protein (RAMP) 1, 2, or 3 receptor complexes [65].

3.3.1. CGRP

CGRP is a 37-amino-acid neuropeptide that is mainly released from sensory nerve terminals and widely distributed in the central and peripheral nervous systems, as well as various organs, including the cardiovascular system [65].

CGRP exhibits antioxidant and anti-inflammatory properties in vitro. In high glucose-treated ECs, CGRP increased the NO production as well as the eNOS expression and decreased oxidative injury by inhibiting ERK1/2-NOX4 [66]. CGRP also exhibited its antioxidant effect by blocking the Src/signal transducers and activation of transduction-3 (STAT3) signaling pathway [67] and attenuated ROS-dependent apoptosis by inhibiting the calcium/calmodulin-dependent protein kinase II (CaMKII)/cAMP-responsive element-binding protein (CREB) signaling pathway in Ang II-treated VSMCs [68]. Additionally, a disintegrin and metalloproteinase domain-containing protein (ADAM17), also known as tumor necrosis factor-α- (TNF-α-) converting enzyme, was found to be involved in the effect of CGRP against VSMC inflammation though the epidermal growth factor receptor (EGFR)-ERK1/2 pathway [69].

CGRP induces vasodilation mainly by directly binding to the receptor complex formed by RAMP1 and CRLR. As compared with young controls, CGRP content was significantly decreased in the resistance arteries and plasma of middle-aged female rats. However, chronic perfusion of estradiol-17β to ovariectomized rats significantly enhanced CGRP and its receptor RAMP1 and thus reduced blood pressure, which suggest that the content and effect of CGRP was regulated by female sex steroid [70]. The endothelium-dependent vasodilator responses to CGRP were significantly decreased in rats during aging, which may be related to the elevation of endogenous asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (eNOS) inhibitor [71]. However, CGRP could also exert cardiovascular protective effects independently of NO. In a mice model of cardiovascular disease associated with endothelial dysfunction and impaired NO production, the endogenous and exogenous CGRP were able to restore blood pressure even when NO synthesis was blocked [72].

CGRP has been reported to have beneficial effects in hypertensive and heart failure patients. Struthers et al. [73] infused human CGRP into normal volunteers, which caused a significant decrease in diastolic pressure and an increase in heart rate. Similarly, prolonged CGRP infusion in patients with congestive heart failure showed significant decreases in arterial pressure as well as in systemic vascular resistance and increase in cardiac output. These studies raised the possibility that CGRP is a potent endogenous vasodilator and a critical physiological regulator of hemodynamics [74]. In addition, the antihypertensive drug olmesartan could exert its vasoprotective effect in hypertensive patients partly via increased CGRP-mediated improvement of endothelial dysfunction, likely due to the increased number of circulating EPCs [75]. The effective dose of CGRP in cardiovascular-related diseases and the longer-lasting CGRP agonists require further study (Figure 4).

Figure 4

The mechanisms of CGRP in protecting against EC and VSMC injury. In ECs, CGRP improves endothelial function by increasing eNOS/NO expression, upregulating telomerase activity, and inhibiting ERK1/2-NOX4 via binding to its receptor complex CRLR/RAMP1. In VSMCs, CGRP attenuates apoptosis by inhibiting the CaMKII/CREB signaling pathway, inhibiting oxidative stress by blocking the Src/STAT3 signaling pathway, and protecting against inflammation via the EGFR-ERK1/2 pathway. Abbreviations: CGRP: calcitonin gene-related peptide; CRLR: calcitonin receptor-like receptor; RAMP: receptor activity-modifying protein; eNOS: endogenous nitric oxide synthase; NO: nitric oxide; ERK: extracellular regulated protein kinase; NOX: NADPH oxidase enzyme; CaMKII: calmodulin-dependent protein kinase II; CREB: cAMP-responsive element-binding protein; STAT3: signal transducers and activators of transduction-3; EGFR: epidermal growth factor receptor; ECs: endothelial cells; VSMCs: vascular smooth muscle cells.

3.3.2. Adrenomedullin (AM)

AM is a 52 amino acid multifunctional peptide discovered in 1993 that shows strong cardiovascular protective effects. High levels of AM are found in the adrenal medulla, heart, lung, and kidney. In addition, AM has been shown to circulate in plasma, and circulating AM is secreted mainly from vascular cells [76].

AM is indispensable for vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure. Shindo et al. [77] showed that targeted null mutation of the AM gene was lethal to mice in utero because of abnormalities of the vascular structure. AM+/- mice survived to adulthood but upregulated blood pressure and decreased NO production, which suggest that AM exerts an effect on blood pressure via an NO-dependent pathway [77]. Similarly, Iring et al. [78] reported that the mechanosensitive cation channel PIEZO1 mediated the fluid shear stress-induced release of AM from ECs in hypertension. The released AM then activated the AM receptor/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, which led to eNOS phosphorylation and thereby promoted NO formation to regulate vascular tone and blood pressure. AM maintains vascular homeostasis via binding to its receptor complexes CRLR/RAMP2 or CRLR/RAMP3. Most EC-specific RAMP2 KO mice (EC-RAMP2-/-) died perinatally. With aging, EC-RAMP2-/- mice showed increased oxidative stress and accelerated vascular senescence [79]. In a wire-induced vascular injury model, the RAMP2+/- vessels showed greater inflammation and oxidative stress than vessels from wild type (WT) mice [80]. AM deficiency exacerbated ischemic brain injury in old mice. The aged AM+/- mice have increased white matter damage after prolonged hypoperfusion compared to WT mice, which was related to oxidative stress induced by AM deletion [81]. In RAMP2+/- mice subjected to MCAO, recovery of cerebral blood flow was slower than in WT mice. Pathological analysis revealed a higher level of oxidative stress and less compensatory capillary growth in RAMP2+/- mice [82]. Taken together, these results indicate that the AM-RAMP2 system is a key determinant of vascular homeostasis from the prenatal stage through adulthood.

AM induces beneficial hemodynamic and myocardial changes in patients with heart failure. AM infusion significantly reduced mean arterial pressure and systemic vascular resistance without changing heart rate and increased cardiac output in acute heart failure patients [83]. In addition, in patients with congestive heart failure, AM also decreased mean arterial pressure and increased heart rate [84]. Age was a significant, independent variable for the plasma level of AM in the general population. The plasma level of AM increased with aging, suggesting possible relationships between the plasma AM level and age-related changes in the cardiovascular system [85] (Figure 5).

3.3.3. Intermedin (IMD)

IMD is an autocrine/paracrine biologically active peptide discovered in 2004. The human IMD gene encodes a prepro-peptide of 148 amino acids. Proteolytic processing of a larger IMD precursor yields a series of biologically active C-terminal fragments, IMD_1-53, IMD_1-47, and IMD_8-47. IMD_1-53 may be the main active fragment of IMD [86]. IMD elicits its biological actions via nonselective interactions with different combinations of CRLR and the 3 RAMPs. In recent years, growing evidence has indicated that IMD is a vital bioactive peptide maintaining vascular homeostasis [86, 87].

We previously found that IMD expression was significantly decreased in old rat aortas. In addition, IMD-deficient mouse VSMCs showed senescence features coinciding with osteogenic transition compared with WT mouse VSMCs [88]. Mechanistically, the antiaging factor SIRT1 mediated the inhibitory effects of IMD on aging-associated vascular calcification [88], while in renal failure-related vascular calcification, the protective role of IMD was mainly mediated by another antiaging factor, α-klotho [89]. Moreover, IMD_1-53 also inhibited the progression of atherosclerotic lesions, plaque vulnerability [90], and calcification [91] in ApoE-/- mice. Furthermore, our study demonstrated that IMD_1-53 protected against atherosclerosis and stabilized the lesions by inhibiting ERS-C/EBP-homologous protein- (CHOP-) mediated macrophage apoptosis, and the subsequent NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome triggered inflammation [90, 91].

In an Ang II-induced ApoE-/- mouse model of AAA, IMD_1-53 significantly reduced the incidence of AAAs. Mechanistically, IMD_1-53 attenuated oxidative stress and subsequent inflammation and VSMC apoptosis by inhibiting NOX4, a ROS generating NADPH oxidase enzyme [92]. In addition, we found that inhibition of Notch1-mediated inflammation by IMD could also be involved in its protection against AAAs [93]. Meanwhile, Li et al. [94] reported that IMD attenuated Ang II-induced vascular collagen remodeling by inhibiting the phosphorylation of Akt and MAPK. Although IMD is considered to be a potent cardiovascular protective factor, there are still challenges to promote the clinical application of IMD. The details of the biological effect of different IMD fragments and the enzymes responsible for its degradation are still to be defined (Figure 6).

Figure 6

The mechanisms of IMD in attenuating vascular aging-related diseases. By binding to CRLR and three RAMPs nonselectively, IMD inhibits VSMC osteogenic transdifferentiation, macrophage and VSMC apoptosis, oxidative stress, and inflammation via different signaling pathways, such as cAMP/PKA, ERS-CHOP, and PI3K/Akt, and thus protects against vascular aging-related diseases. Abbreviations: IMD: intermedin; CRLR: calcitonin receptor-like receptor; RAMP: receptor activity-modifying protein; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; SIRT1: sirtuin1; VSMC: vascular smooth muscle cell; ERS: endoplasmic reticulum stress; CHOP: C/EBP-homologous protein; NLRP3: NOD-like receptor family pyrin domain containing 3; PI3K: phosphatidylinositol 3 kinase; Akt: protein kinase B; NOX4: NADPH oxidase enzyme 4.

3.4. C-Type Natriuretic Peptide (CNP)

CNP, the third member of the natriuretic peptide family, is a potent vasorelaxative peptide of 22 amino acids. As an autocrine and paracrine mediator, CNP can be produced and secreted by vascular ECs, VSMCs, and fibroblasts and governs a wide range of cardiovascular effects [95, 96].

CNP exerts its regulatory effects on the cardiovascular system via two cognate receptors, natriuretic peptide receptor B (NPR-B, also called guanylate cyclase B (GC-B)) and NPR-C, which induce activation of distinct signaling pathways. CNP stabilized resident perivascular mast cells at baseline and prevented their excessive activation via GC-B/cGMP signaling in mice after acute ischemia-reperfusion [97]. In addition, NPR-C in ECs mediated the role of CNP in angiogenesis and vascular remodeling in response to ischemia. These effects of CNP/NPR-C on ischemia were dependent on the activation of ERK1/2 and PI3K/Akt signaling pathways [98]. Besides, the CNP system plays a crucial role in regulating blood pressure. The vasodilatory effects of CNP on the microvasculature were endothelium-independent, which were mediated by GC-B/cGMP signaling in VSMCs of distal arterioles and capillary pericytes. These data indicated that the GC-B receptor in VSMCs and pericytes is essential for CNP to maintain normal microvascular resistance and blood pressure [99]. However, another research reported that VSMC-specific GC-B KO mice exhibited systemic blood pressure similar to control mice [100]. The mechanism of CNP/GC-B system in regulating blood pressure remains to be confirmed. Moyes et al. [96] found that administration of small-molecule NPR-C agonists promoted vasorelaxation of isolated resistance arteries and reduced blood pressure in WT animals. Treatment with CNP effectively attenuated vascular remodeling and reduced systolic blood pressure in hypertensive rats and decreased both proinflammatory and profibrotic cytokines [101]. In addition, CNP activated the vascular NO system and exerted an antioxidant effect in the aortic tissue of both hypertensive rats and normotensive rats [101]. Impaired local endogenous CNP may be associated with increased vascular calcium deposition in rat aortas with vascular calcification [102]. Administration of CNP greatly reduced vascular calcification by preventing the osteogenic transition of contractile VSMCs [102]. These results show that CNP not only regulates blood pressure but also attenuates vascular damage.

A couple of clinical studies have measured plasma CNP level as a prognostic biomarker for CVDs [103–105]. Bubb et al. [98] revealed that vascular ischemia was associated with reduced levels of CNP and NPR-C, which suggest that CNP/NPR-C signaling might be critical to a proangiogenic host defense response to ischemia. In old patients with heart failure, cardiac and systemic CNP levels were increased and related to clinical severity [104]. In addition, another research found that highest concentrations of CNP identified a high-risk phenotype that included cardiovascular comorbidities and left ventricle dysfunction [106]. However, the half-life of CNP is short and circulating levels of CNP are very low. The N-terminal part (NT) of proCNP (NT-proCNP) can be more easily measured compared with CNP. Prickett et al. [105] showed that NT-proCNP largely reflected vascular integrity and was an independent predictor of both mortality and cardiac readmission in individuals with unstable angina. Taken together, targeting the CNP and its receptor pathways may therefore provide a tangible pharmacological approach to improve cardiovascular disorders (Figure 7).

3.5. Cortistatin (CST)

CST, a recently detected endogenous bioactive peptide, is highly expressed in the cerebral cortex and exerts an inhibitory effect on cortical activity [107]. CST and its receptors are widely distributed not only in the central nervous system, endocrine system, and immune system but also in the cardiovascular system. CST can activate somatostatin receptors (SSTRs), growth hormone secretagogue receptor 1a (GHSR1a), or the Mas-related gene X-2 receptor (MrgX2) to exert biological effects [107].

In vitro, CST inhibited the osteogenic differentiation of VSMCs in induced calcification by mitigating ERS, as shown by decreased protein expression of glucose-regulated protein 94 (GRP94) and CHOP [108], as well as the glycogen synthase kinase 3β (GSK3β)/β-catenin and PKC signaling pathways [109]. CST could ameliorate Ang II-stimulated VSMC proliferation and migration by inhibiting autophagy through its receptors SSTR3 and SSTR5 [110] and by inhibiting the MAPK family, including ERK1/2, p38 MAPK, JNK, and ERK5 pathways [111]. These results indicate that CST could play a critical role in regulating VSMC function under pathological conditions.

In vivo, CST also plays an important role in vascular homeostasis. Exogenous CST remarkably attenuated neointimal formation, while CST-deficient mice developed higher neointimal hyperplasic lesions than WT mice [112]. It was reported that CST treatment significantly improved hemodynamic values and arterial compliance in rats with vascular calcification, with decreased calcium deposition, alkaline phosphatase (ALP) activity, and type III sodium-dependent phosphate cotransporter-1 (Pit-1) level in aortic tissues. These effects were mediated by GHSR1a rather than SSTRs or MrgX2 [113]. Treatment with CST reduced the number and size of atherosclerotic plaques and inflammatory responses in atherosclerosis in mice. Mechanistically, CST reduced the capacity of ECs to bind and recruit immune cells to the plaques and enhanced cholesterol efflux from macrophages, thus inhibiting the formation of foam cells [114]. Additionally, CST administration significantly suppressed the incidence and severity of AAA formation in mice by alleviating the inflammatory cytokines and ROS levels, expression of matrix metalloproteinase (MMP)2 and MMP9, and cell apoptosis. Mechanistic studies showed that the protective effects of CST in AAAs were related to the blocking of ERK1/2 signaling pathways [115].

At present, increasing clinical evidence indicated the potential role of CST in the regulation of CVDs. The circulating CST level was significantly increased in patients with coronary heart disease [112]. Duran-Prado et al. [112] demonstrated that VSMCs from human atherosclerotic plaques highly expressed CST, which indicates that CST could play an important role in atherosclerosis in human. However, there is still a long way to extend CST to clinical treatment (Figure 8).

Figure 8

The mechanisms of CST in attenuating vascular dysfunction. CST activates three kinds of receptor including SSTRs, GHSR, and MrgX2 to exert different biological effects such as inhibit VSMC osteogenic transdifferentiation, proliferation, or apoptosis. Abbreviations: CST: cortistatin; ERS: endoplasmic reticulum stress; GHSR: growth hormone secretagogue receptor; GSK3β: glycogen synthase kinase 3β; MAPK: mitogen-activated protein kinase; MrgX2: Mas-related gene X-2 receptor; PKC: protein kinase C; SSTR: somatostatin receptor; VSMC: vascular smooth muscle cell.

3.6. Ghrelin

Ghrelin is a 28 amino acid peptide and functions as a natural endogenous ligand for GHSR. Ghrelin is produced by the stomach, heart, lung, and kidney and has extensive physiological effects, such as stimulating growth hormone secretion, promoting food intake, and maintaining energy homeostasis. Emerging evidence has shown favorable effects of ghrelin on cardiovascular function via either growth hormone-dependent or -independent mechanisms [116, 117].

The plasma concentration of ghrelin significantly elevated in aged mice, but exogenous administration of ghrelin failed to prolong survival in klotho-deficient mice, a model of accelerated aging, suggesting the existence of ghrelin resistance in aging process [118]. However, rikkunshito and atractylodin, two ghrelin signaling potentiators, markedly attenuated calcification and focal atrophy of cardiac muscle and prolonged survival in three mouse models of aging via the GHSR-cAMP-CREB-SIRT1 pathway [118].

Emerging evidence has shown favorable effects of ghrelin on cardiovascular function [116, 117]. Ghrelin rescued the activity of SIRT1 and the expression of superoxide dismutase-2 (SOD-2), a primary enzymatic antioxidant defense against ROS production, and resulted in great attenuation of EC senescence in mice [119]. Ghrelin could inhibit VSMC calcification by downregulating receptor activator of nuclear factor kappa B ligand (RANKL) level and increasing osteoprotegerin (OPG) expression [120] and by improving autophagy through AMPK activation [121]. In addition, ghrelin overexpression prevented high-fat diet-induced lipid accumulation in vessels by decreasing oxidative stress and thus results in improved vascular function and reduced plaque formation [122]. Furthermore, ghrelin decreased the expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) and reduced monocyte chemotactic protein 1 (MCP-1) expression, likely contributing to its protective effect in neovascularization and plaque vulnerability at an advanced stage of atherosclerosis [123].

A clinical study documented a significant negative association between ghrelin and carotid artery intima-media thickness in females with the metabolic syndrome, which suggest its active involvement in prevention of the atherosclerosis [124]. Besides, the serum ghrelin level may be a predictor of diabetic vascular calcification, because there was a negative correlation between calcium content and the ghrelin level in diabetic patient serum [120]. Moreover, exogenous ghrelin intra-arterial infusion increased endogenous antioxidant capacity, decreased levels of lipoperoxide, malondialdehyde, and phosphorylated p47, and restored the NO availability in small vessels from hypertensive patients [125]. Collectively, ghrelin may be beneficial for the restoration of impaired cardiovascular function associated with aging (Figure 9).

Figure 9

The protective effects of ghrelin on vascular aging. Ghrelin attenuates vascular calcification, inflammation, and senescence by multiple pathways through combination with the receptor GHSR. Abbreviations: AMPK: AMP-activated protein kinase; EC: endothelial cell; eNOS: endogenous nitric oxide synthase; GHSR: growth hormone secretagogue receptor; MCP-1: monocyte chemotactic protein 1; NO: nitric oxide; OPG: osteoprotegerin; RANKL: receptor activator of nuclear factor kappa B ligand; ROS: reactive oxygen species; SIRT1: sirtuin1; SOD-2: superoxide dismutase-2; VSMC: vascular smooth muscle cell.

3.7. Glucagon-Like Peptide-1 (GLP-1)

GLP-1 is an incretin hormone that was first discovered as a regulator of insulin release from β-cells in the pancreas. As a hormone mainly secreted postprandially by intestinal L-cells, GLP-1 has multiple functions, from the regulation of insulin secretion to the control of glucose homeostasis and modulation of autonomic nervous system activity [126, 127]. GLP-1 exerts its effects through binding with GLP-1 receptor (GLP-1R), which is widely expressed in islet cells, lung, brain, kidney, and cardiovascular systems [127]. Currently, it is well acknowledged that GLP-1 exerts cardiovascular protective effects, such as alleviation of myocardial infarction [128], relaxation of vascular smooth muscle [129–131], improvement of endothelial dysfunction [132, 133], and inhibition of vascular senescence [130, 132, 134].

GLP-1/GLP-1R system may play an important role in VSMC senescence. GLP-1 treatment led to a decreasing expression of senescence markers in VSMCs treated with doxorubicin, a chemotherapeutic agent used in cancer treatment, which suggests that GLP-1 is a promising candidate for patients suffering from late doxorubicin cardiovascular toxicity [130]. Pretreatment with exendin-4, a specific ligand for GLP-1R, significantly attenuated Ang II-induced generation of H₂O₂ and inhibited expression of p53 and p21 and subsequent VSMC senescence by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. However, these effects were reversed in the presence of exendin (9-39), a GLP-1R antagonist [135]. Similarly, Zhou et al. [136] also demonstrated that exendin-4 could attenuate Ang II-induced ROS production and VSMC senescence. Mechanistically, exendin-4 increased the acetylation of Nrf2 and the recruitment of the transcriptional coactivator CREB binding protein (CBP) to Nrf2, which contributed to the upregulation of the antioxidant genes HO-1 and NADPH quinone oxidoreductase-1 (NQO-1) [136]. Dulaglutide, a specific GLP-1R agonist, significantly inhibited oxidized low-density lipoprotein- (Ox-LDL-) induced oxidative stress, mitochondrial dysfunction, and proinflammatory cytokine expression by increasing Krüppel-like factor 2 (KLF2) in ECs [137].

In vivo, exendin-4 had a strong dilatory effect on cortical arterioles and effectively increased cerebral blood flow via the cAMP/PKA signaling pathway in ischemic rats [138]. Exendin-4 also ameliorated BBB breakdown, reduced the infarct area, and decreased inflammation by reducing astrocyte-derived VEGF-A expression through Janus kinase 2 (JAK2)/STAT3 signaling in rat ischemic brain tissues [139]. Dipeptidyl-peptidase (DPP-4) is an enzyme that degrades native GLP-1. Mice that underwent ischemic surgery showed increased levels of DPP-4 but decreased levels of GLP-1 and antiaging factors in ischemic vessels [134]. However, DPP-4 inhibition or GLP-1R activation attenuated aortic senescence and promoted neovascularization via the upregulation of adiponectin/AdopR1 and PPAR-γ/PGC-1α signaling [134]. Diabetic rats that received exenatide, a GLP-1 analog, or sitagliptin, a DPP-4 inhibitor, showed a significant elevation of aortic endothelial function but reduced oxidative stress and inflammatory cytokine levels [140]. Notably, inhibition of RhoA/Rho associated coiled coil forming protein kinase (ROCK)/NF-κB/IκB α signaling pathway and activation of AMPK may also contribute to the protective effects of GLP-1 on aortic endothelium in diabetes [140]. Consistently, Taguchi et al. [129] showed that GLP-1 significantly enhanced endothelial-dependent relaxation in diabetic aortas, which could be mediated through activation of the AMPK/Akt pathway. In addition, GLP-1 reverses Ang II-induced vascular remodeling by decreasing expression of MMP1 through inhibition of the ERK1/2-NF-κB signaling [131]. Treatment with alogliptin, a DPP4 inhibitor, or liraglutide, a GLP-1R agonist, decreased blood pressure, vascular wall thickness, and vascular collagen levels in SHRs [131]. Liraglutide treatment also alleviated vascular fibrosis, inflammation, oxidative stress, and endothelial dysfunction via GLP-1R in hypertension [133].

Currently, the therapeutic drugs targeting the GLP-1 system have been widely used in clinical practice. GLP-1 receptor agonists (i.e., exenatide, liraglutide, semaglutide, and lalutide) and DPP-4 inhibitors (i.e., saxagliptin, sitagliptin, vigliptin, and liragliptin) have become fundamental treatment options for type 2 diabetes. Clinical studies showed that the potential cardiovascular protective effects of GLP-1 can be attributed to decreased blood pressure and direct effects on vascular cells. A research in patients with type 2 diabetes mellitus and impaired renal function showed that liraglutide decreased systemic vascular resistance and exerted vasodilatory effect in earlier chronic kidney disease [141]. The addition of semaglutide to standard of care was associated with a decrease in 10-year cardiovascular disease risk [142]. The elderly diabetic patient population treated with GLP-1 showed significant in reduction of vascular inflammation and blood glucose, as well as improvement of vascular endothelial function [143]. All these results indicate that GLP-1 participates in the regulation of vascular aging-related diseases and GLP-1R agonists could be recommended for people with diabetes and high cardiovascular risks (Figure 10).

Figure 10

The mechanisms of GLP-1 in protecting against vascular aging. GLP-1 is mainly secreted from intestinal L-cells and exerts its vascular protective effects by binding to its receptor GLP-1R expressed in the vessels. GLP-1 attenuated VSMC senescence, EC senescence, ECM remodeling, inflammation, and oxidative stress via activating multiple signaling pathways. Abbreviations: Akt: protein kinase B; AMPK: AMP-activated protein kinase; cAMP: cyclic adenosine monophosphate; CBP: CREB binding protein; EC: endothelial cell; ERK: extracellular regulated protein kinase; ECM: extracellular matrix; eNOS: endogenous nitric oxide synthase; GLP-1: glucagon-like peptide-1; KLF2: Krüppel-like factor 2; MMP: matrix metalloproteinase; NF-κB: nuclear factor kappa-B; Nrf2: nuclear factor-erythroid 2-related factor 2; PI3K: phosphatidylinositol 3 kinase; PKA: protein kinase A; RAGE: receptor for advanced glycation end products; ROCK: Rho associated coiled coil forming protein kinase; SIRT1: sirtuin1; VSMC: vascular smooth muscle cell.

3.8. Humanin (HN)

HN is the first identified mitochondrial-derived antiapoptotic peptide that is best known for its ability to suppress neuronal cell death caused by Alzheimer’s disease-specific insults, including both amyloid-β peptides and familial Alzheimer’s disease-causative genes [144]. HN acts as a ligand for two different types of receptors: the seven-transmembrane G protein-coupled receptor formyl peptide receptor-like 1 (FPRL1) and a trimeric receptor consisting of the ciliary neurotrophic factor receptor (CNTFR), the cytokine receptor WSX-1, and the transmembrane glycoprotein 130 (gp130) (CNTFR/WSX-1/gp130). In recent years, a large number of studies have revealed the beneficial properties of HN and its analog S14G-HN (HNG), including antioxidative stress, anti-inflammatory responses, and antiapoptotic effects, in age-related disorders [145].

Early studies demonstrated that HN is expressed in the EC layer of the vascular wall [146, 147] but not in the VSMC layer [146]. Therefore, in vitro studies on HN are mostly focused on ECs. In high glucose-treated HUVECs, HN increased the expression of KLF2 as well as its target gene eNOS but inhibited the secretion of TNF-α, IL-1β, vascular cell adhesion molecule-1 (VCAM-1), and E-selectin and the attachment of the monocyte cells to HUVECs. However, knockdown of KLF2 abolished these effects [148]. Thus, KLF2 may play a critical role in mediating the protective effects of HN in endothelial function. In addition, HN inhibited the activation of the NLRP3 inflammasome and endothelial inflammation via AMPK pathway and suppressed oxidative stress by downregulating the expression of NOX2 induced by free fatty acids in ECs [149]. Exogenous addition of HN to EC cultures was shown to be protective against Ox-LDL-induced apoptosis in response to oxidative stress [146]. The effect of HN on reducing lipid aggregation and EC apoptosis could be depicted in a lectin-like Ox-LDL receptor-1 (LOX-1-) dependent manner [150]. Furthermore, HNG restored the activity of the Ox-LDL-induced damaged lysosomal enzyme cathepsin D, promoting autophagic degradation of Ox-LDL in HUVECs, which may be mediated by its membrane protein receptor FPRL1 [151]. HNG also protected cell survival and suppressed inflammatory cytokines induced by oxygen deprivation via inhibition of the NF-κB pathway in mouse brain ECs [152]. Although it was considered that HN was not expressed in VSMCs, HN did protect human cerebrovascular SMCs against amyloid β-protein-induced cell toxicity, with diminishing degradation of α-actin and cell death [153].

HN also attenuated microvascular remodeling, inflammation, and apoptosis in ApoE-/- mice [154]. In a murine MCAO stroke model, HNG ameliorated cerebral infarction and suppressed the production of inflammatory cytokines [152]. Furthermore, HN analogue HNGF6A prevented endothelial dysfunction and potently delayed progression of atherosclerosis in ApoE-/- mice fed on a high cholesterol diet. These effects were associated with antioxidative stress, antiapoptosis, and increased eNOS expression [147].

Circulating HN level significantly decreased in patients with coronary endothelial dysfunction, while it was positively correlated with improved coronary blood flow [155]. Besides, the improvement of cognitive function in patients with vascular dementia may be related to elevated serum HN levels [156]. Furthermore, Muzumdar et al. [157] demonstrated the circulating level of HN was decreased with age in Alzheimer’s disease and type 2 diabetes mellitus patients. In contrast, a recent study [158], in which plasma HN concentrations were evaluated in 693 volunteers of different ages, demonstrated that plasma levels of HN were positively correlated with age in humans and become maximal in centenarians. These studies are consistent with the concept that HN could be considered as a marker of biological age (Figure 11).

Figure 11

The beneficial properties of HN in vascular cell damage. HN exerts anti-inflammatory, antioxidative stress, and antiapoptosis effects via its receptors FPRL1 and the complex CNTFR/WSX-1/gp130. The target molecules of HN include KLF2, NOX2, and NLRP3. Abbreviations: AMPK: AMP-activated protein kinase; CNTFR: ciliary neurotrophic factor receptor; eNOS: endogenous nitric oxide synthase; FPRL1: formyl peptide receptor-like 1; gp130: glycoprotein 130; HN: humanin; KLF2: Krüppel-like factor 2; NF-κB: nuclear factor kappa-B; NLRP3: NOD-like receptor family pyrin domain containing 3; NOX2: NADPH oxidase enzyme 2.

Endogenous vasoactive peptides are a serial of dynamical molecules in modulation of cardiovascular and body fluid homeostasis, providing potential intervention targets for vascular aging-related diseases. Despite intensive study of vasoactive factors at the molecular level, there are still lack of effective pharmacological approach to manipulate these systems. The main promise of vasoactive peptides as diagnostic and therapeutic tools are their property of changing dynamically with diseases and possess a wide range of biological effects. Recent studies showed significantly altered expression profiles of peptides in the process of vascular aging and strongly suggest that a decline in antivascular aging peptides may be associated with the progression of age-related vascular diseases [39, 98, 155]. As specific antibodies against these peptides have been developed, their plasma levels could be quantified by radioimmunoassay and enzyme-linked immunosorbent assay (ELISA). Additionally, variously combined use of a panel of peptides may increase the diagnostic accuracy in patients of vascular diseases.

In addition to being used as potential biomarkers, endogenous vasoactive peptides could also be served as a therapeutic tool for treatment of vascular diseases. So far, the RAS is the best studied vasoactive system, and the altered expression of its components may contribute to ACE/Ang II/AT1R-mediated pathogenesis of vascular diseases. Clinical data have shown beneficial effects in CVD patients treated with ARBs or ACE inhibitors. Similarly, drugs that target fundamental aging processes, such as endothelia dysfunction, VSMC proliferation, oxidative stress, and inflammation, may have the potential to prevent/delay a range of vascular pathologies and other age-related diseases simultaneously. Recently a variety of vasoactive peptides have emerged from basic research and translational studies that may target aging processes. As indicated in Table 1, many vasoactive peptides show anti-inflammatory and antioxidant effects, suppress VSMC proliferation, and promote endothelial NO production. Thus, the interventions with these peptides can be applied for prevention of age-related vascular diseases, and much work is needed to develop drugs that target multiple vasoactive pathways controlling vascular aging. Additionally, the peptide mimics and their receptor agonist/antagonists (Figure 12) should be studied in more depth in prospective clinical research in elderly patients with vascular disorders.

Figure 12

Some common vasoactive peptides and their receptors, agonists, and antagonists. Abbreviations: AM: adrenomedullin; Ang-(1-7): angiotensin-(1-7); APJ: apelin receptor; AT2R: angiotensin type 2 receptor; CGRP: calcitonin gene-related peptide; CNTFR: ciliary neurotrophic factor receptor; CNP: C-type natriuretic peptide; CRLR: calcitonin receptor-like receptor; CST: cortistatin; FPRL1: formyl peptide receptor-like 1; GHSR: growth hormone secretagogue receptor; GLP-1: glucagon-like peptide-1; gp130: glycoprotein 130; HN: humanin; IMD: intermedin; MrgX2: Mas-related gene X-2 receptor; NPR: natriuretic peptide receptor; RAMP: receptor activity-modifying protein; SSTR: somatostatin receptor.

Currently, clinical studies revealed that major challenges faced by those vasoactive peptides are due to their rapid turnover in vivo and low efficiency for passing through the BBB. Thus, extensive effort is still required to overcome those unfavorable factors and to develop drug candidates with more efficiency, persistency, and safety. Moreover, development of new drug delivery system to penetrate the BBB and to continuously release effective peptide is also a prospective strategy.

5. Conclusions

Endogenous vasoactive peptides are now recognized as having prominent cardiovascular distribution and various modulatory effects on vascular aging-related diseases. Altered levels of these peptides in circulating blood and/or cardiovascular tissues are closely linked to age-related vascular diseases. Moreover, emerging animal studies indicate that these peptides are actively involved in the modulation of oxidative stress, inflammation, apoptosis, and vascular remodeling during aging. Thus, endogenous vasoactive peptides, alone or in various combinations, are candidate biomarkers for predicting CVDs, which may be useful for earlier detection. Vasoactive peptides, their receptors, and the proteases that degrade the same peptides may become special targets of new specific pharmacologic approaches. However, there is still an urgent need for persuasive statistical evidence in animals and clinical trials as well as site-specific studies to elucidate the generalized and precise mechanisms underlying the effects of different vasoactive peptides in vascular aging and to develop effective and safe treatments for age-related vascular diseases.

6. Future Research Directions

In recent years, quantitative peptidomic studies are widely used for peptide investigation with the development of mass spectrometry technology. The emergence of vasoactive peptides indicated a new perspective toward exploring the pathogenesis of vascular aging-related diseases. And significant progress has been achieved in studying the effects of vasoactive peptides on aging-induced alterations in vascular function and phenotype and vascular disorders; however, only a limited number of vasoactive peptides have demonstrated significant diagnostic and/or therapeutic impact. Hence, research efforts should continue to develop innovative strategies based on recent achievements in the biology of vascular aging, as well as in properties and effects of vasoactive peptides, to improve the diagnosis and treatment of aging-related vascular diseases. Moreover, deeper insights into the pathophysiology of vascular aging and the interaction of processes of aging and vascular diseases may led to the discovery of novel molecular targets for the peptides. The research field that is likely to solve problems concerning the mechanism of effects, control of release, and significance of a wide range of endogenous peptides in cardiovascular regulation and pathogenesis of vascular aging needs to be explored further. The role of specific signal transduction pathways mediated by these vasoactive peptides in the process of vascular aging should be better elucidated, which may intensify pharmacological drugs that interfere with the peptides net system at multiple sites. In future, studies using bioinformatics technology like single-cell gene expression analysis should also lead to improved understanding of cellular and functional heterogeneity in regulation of vascular aging by these peptides. Researchers should perform more site-specific studies to elucidate the precise mechanisms of the peptides in vascular diseases. Finally, better joint research of preclinical studies on vascular aging and human investigations is also urgently needed to yield consistent incremental clinical benefits of endogenous vasoactive peptides.

Data Availability

All data used have been reported in the article.

Conflicts of Interest

The authors declare that they have no competing interests.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 81600210 and 82270503 to WW Lu and Nos. 31872790 and 32071113 to YF Qi), the Research Foundation of Soochow University (No. NH13400121), and the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

References

Y. T. Ghebre, E. Yakubov, W. T. Wong et al., “Vascular aging: implications for cardiovascular disease and therapy,” Translational medicine (Sunnyvale, Calif.), vol. 6, no. 4, p. 183, 2016.
View at: Publisher Site | Google Scholar
Z. Ungvari, S. Tarantini, A. J. Donato, V. Galvan, and A. Csiszar, “Mechanisms of vascular aging,” Circ Res., vol. 123, no. 7, pp. 849–867, 2018.
View at: Google Scholar
X. Xu, B. Wang, C. Ren et al., “Recent progress in vascular aging: mechanisms and its role in age-related diseases,” Aging and Disease, vol. 8, no. 4, pp. 486–505, 2017.
View at: Publisher Site | Google Scholar
M. Packer and J. J. V. McMurray, “Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure,” The Lancet, vol. 389, no. 10081, pp. 1831–1840, 2017.
View at: Publisher Site | Google Scholar
T. Peltonen, P. Ohukainen, H. Ruskoaho, and J. Rysa, “Targeting vasoactive peptides for managing calcific aortic valve disease,” Annals of Medicine, vol. 49, no. 1, pp. 63–74, 2017.
View at: Publisher Site | Google Scholar
P. Khodabakhsh, A. Asgari Taei, M. Mohseni et al., “Vasoactive peptides: their role in COVID-19 pathogenesis and potential use as biomarkers and therapeutic targets,” Archives of Medical Research, vol. 52, no. 8, pp. 777–787, 2021.
View at: Publisher Site | Google Scholar
E. J. Benjamin, P. Muntner, A. Alonso et al., “Heart disease and stroke statistics-2019 update: a report from the American Heart Association,” Circulation, vol. 139, no. 10, pp. e56–e528, 2019.
View at: Publisher Site | Google Scholar
H. Wan, G. Daniel, and K. Paul, An aging world: 2015, US Census Bureau, 2016.
R. Menghini, R. Stohr, and M. Federici, “MicroRNAs in vascular aging and atherosclerosis,” Ageing Res Reviews, vol. 17, pp. 68–78, 2014.
View at: Publisher Site | Google Scholar
T. J. Guzik and R. M. Touyz, “Oxidative stress, inflammation, and vascular aging in hypertension,” Hypertension, vol. 70, no. 4, pp. 660–667, 2017.
View at: Publisher Site | Google Scholar
E. G. Lakatta and D. Levy, “Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease,” Circulation, vol. 107, no. 1, pp. 139–146, 2003.
View at: Publisher Site | Google Scholar
M. Cortes-Canteli and C. Iadecola, “Alzheime’s Disease and Vascular Aging,” Journal of the American College of Cardiology, vol. 75, no. 8, pp. 942–951, 2020.
View at: Publisher Site | Google Scholar
H. Xu, S. Li, and Y. S. Liu, “Roles and mechanisms of DNA methylation in vascular aging and related diseases,” Frontiers in Cell and Developmental Biology, vol. 9, p. 1695, 2021.
View at: Publisher Site | Google Scholar
C. Lopez-Otin, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “The hallmarks of aging,” Cell, vol. 153, no. 6, pp. 1194–1217, 2013.
View at: Publisher Site | Google Scholar
F. Piccirillo, M. Carpenito, G. Verolino et al., “Changes of the coronary arteries and cardiac microvasculature with aging: implications for translational research and clinical practice,” Mechanisms of Ageing and Development, vol. 184, p. 111161, 2019.
View at: Publisher Site | Google Scholar
C. Chi, D. J. Li, Y. J. Jiang et al., “Vascular smooth muscle cell senescence and age-related diseases: state of the art,” Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, vol. 1865, no. 7, pp. 1810–1821, 2019.
View at: Publisher Site | Google Scholar
F. Triposkiadis, A. Xanthopoulos, and J. Butler, “Cardiovascular Aging and Heart Failure:,” Journal of the American College of Cardiology, vol. 74, no. 6, pp. 804–813, 2019.
View at: Publisher Site | Google Scholar
G. G. Camici, G. Savarese, A. Akhmedov, and T. F. Luscher, “Molecular mechanism of endothelial and vascular aging: implications for cardiovascular disease,” European Heart Journal, vol. 36, no. 48, pp. 3392–3403, 2015.
View at: Publisher Site | Google Scholar
K. L. Moreau, M. C. Babcock, and K. L. Hildreth, “Sex differences in vascular aging in response to testosterone,” Biology of Sex Differences, vol. 11, no. 1, p. 18, 2020.
View at: Publisher Site | Google Scholar
K. L. Moreau, “Modulatory influence of sex hormones on vascular aging,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 316, no. 3, pp. H522–H526, 2019.
View at: Publisher Site | Google Scholar
S. L. Davison, R. Bell, S. Donath, J. G. Montalto, and S. R. Davis, “Androgen levels in adult females: changes with age, menopause, and oophorectomy,” The Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 7, pp. 3847–3853, 2005.
View at: Publisher Site | Google Scholar
J. J. DuPont, S. K. Kim, R. M. Kenney, and I. Z. Jaffe, “Sex differences in the time course and mechanisms of vascular and cardiac aging in mice: role of the smooth muscle cell mineralocorticoid receptor,” Journal of Physiology-Heart and Circulatory Physiology, vol. 320, no. 1, pp. H169–H180, 2021.
View at: Publisher Site | Google Scholar
L. B. Arendse, A. H. J. Danser, M. Poglitsch et al., “Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure,” Pharmacological Reviews, vol. 71, no. 4, pp. 539–570, 2019.
View at: Publisher Site | Google Scholar
I. Valencia, L. Shamoon, A. Romero, F. De la Cuesta, C. F. Sánchez-Ferrer, and C. Peiró, “Angiotensin-(1-7), a protective peptide against vascular aging,” Peptides, vol. 152, p. 170775, 2022.
View at: Publisher Site | Google Scholar
R. J. Mentz, G. L. Bakris, B. Waeber et al., “The past, present and future of renin-angiotensin aldosterone system inhibition,” International Journal of Cardiology, vol. 167, no. 5, pp. 1677–1687, 2013.
View at: Publisher Site | Google Scholar
M. Wang, J. Zhang, L. Q. Jiang et al., “Proinflammatory profile within the grossly normal aged human aortic wall,” Hypertension, vol. 50, no. 1, pp. 219–227, 2007.
View at: Publisher Site | Google Scholar
M. Wang, J. Zhang, G. Spinetti et al., “Angiotensin II activates matrix metalloproteinase type II and mimics age-associated carotid arterial remodeling in young rats,” The American Journal of Pathology, vol. 167, no. 5, pp. 1429–1442, 2005.
View at: Publisher Site | Google Scholar
K. Hayashi, K. Miyagawa, K. Sato, R. Ueda, and Y. Dohi, “Temocapril, an Angiotensin converting enzyme inhibitor, ameliorates age-related increase in carotid arterial stiffness in normotensive subjects,” Cardiology, vol. 106, no. 3, pp. 190–194, 2006.
View at: Publisher Site | Google Scholar
J. B. Michel, D. Heudes, O. Michel et al., “Effect of chronic ANG I-converting enzyme inhibition on aging processes. II. Large arteries,” American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, vol. 267, no. 1, pp. R124–R135, 1994.
View at: Publisher Site | Google Scholar
A. Romero, A. San Hipolito-Luengo, L. A. Villalobos et al., “The angiotensin-(1-7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation,” Aging Cell., vol. 18, no. 3, p. e12913, 2019.
View at: Publisher Site | Google Scholar
L. A. Villalobos, A. San Hipolito-Luengo, M. Ramos-Gonzalez et al., “The Angiotensin-(1-7)/Mas axis counteracts angiotensin II-dependent and -independent pro-inflammatory signaling in human vascular smooth muscle cells,” Frontiers in Pharmacology, vol. 7, p. 482, 2016.
View at: Publisher Site | Google Scholar
F. Zhang, H. Tang, S. Sun et al., “Angiotensin-(1-7) induced vascular relaxation in spontaneously hypertensive rats,” Nitric Oxide, vol. 88, pp. 1–9, 2019.
View at: Publisher Site | Google Scholar
A. Sousa-Lopes, R. A. de Freitas, F. S. Carneiro et al., “Angiotensin (1-7) inhibits Ang II-mediated ERK1/2 activation by stimulating MKP-1 activation in vascular smooth muscle cells,” International Journal of Molecular and Cellular Medicine, vol. 9, no. 1, pp. 50–61, 2020.
View at: Publisher Site | Google Scholar
S. Bosnyak, R. E. Widdop, K. M. Denton, and E. S. Jones, “Differential mechanisms of ang (1-7)-mediated vasodepressor effect in adult and aged candesartan-treated rats,” International Journal of Hypertension, vol. 2012, Article ID 192567, 9 pages, 2012.
View at: Publisher Site | Google Scholar
F. P. Costa-Fraga, G. K. Goncalves, F. P. Souza-Neto et al., “Age-related changes in vascular responses to angiotensin-(1-7) in female mice,” Journal of the Renin-Angiotensin-Aldosterone System, vol. 19, no. 3, p. 1470320318789332, 2018.
View at: Publisher Site | Google Scholar
G. Yang, G. Istas, S. Hoges et al., “Angiotensin-(1-7)-induced Mas receptor activation attenuates atherosclerosis through a nitric oxide-dependent mechanism in apolipoproteinE-KO mice,” Pflügers Archiv-European Journal of Physiology, vol. 470, no. 4, pp. 661–667, 2018.
View at: Publisher Site | Google Scholar
F. Zhang, S. Li, J. Song, J. Liu, Y. Cui, and H. Chen, “Angiotensin-(1-7) regulates angiotensin II-induced matrix metalloproteinase-8 in vascular smooth muscle cells,” Atherosclerosis, vol. 261, pp. 90–98, 2017.
View at: Publisher Site | Google Scholar
F. Xue, J. Yang, J. Cheng et al., “Angiotensin-(1-7) mitigated angiotensin II-induced abdominal aortic aneurysms in apolipoprotein E-knockout mice,” British Journal of Pharmacology, vol. 177, no. 8, pp. 1719–1734, 2020.
View at: Publisher Site | Google Scholar
V. T. Ribeiro, T. M. E. Cordeiro, R. D. S. Filha et al., “Circulating angiotensin-(1-7) is reduced in Alzheimer's disease patients and correlates with white matter abnormalities: results from a pilot study,” Front Neuroscience, vol. 15, p. 636754, 2021.
View at: Publisher Site | Google Scholar
M. J. Durand, N. S. Zinkevich, M. Riedel et al., “Vascular actions of angiotensin 1-7 in the human microcirculation: novel role for telomerase,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 36, no. 6, pp. 1254–1262, 2016.
View at: Publisher Site | Google Scholar
F. Annoni, F. Moro, E. Caruso, T. Zoerle, F. S. Taccone, and E. R. Zanier, “Angiotensin-(1-7) as a potential therapeutic strategy for delayed cerebral ischemia in subarachnoid hemorrhage,” Frontiers in Immunology, vol. 13, p. 841692, 2022.
View at: Publisher Site | Google Scholar
K. Tatemoto, M. Hosoya, Y. Habata et al., “Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor,” Biochemical and Biophysical Research Communications, vol. 251, no. 2, pp. 471–476, 1998.
View at: Publisher Site | Google Scholar
Y. Zhou, Y. Wang, S. Qiao, and L. Yin, “Effects of apelin on cardiovascular aging,” Frontiers in Physiology, vol. 8, p. 1035, 2017.
View at: Publisher Site | Google Scholar
A. Mughal and S. T. O'Rourke, “Vascular effects of apelin: mechanisms and therapeutic potential,” Pharmacology & Therapeutics, vol. 190, pp. 139–147, 2018.
View at: Publisher Site | Google Scholar
R. Yang, W. Fang, J. Liang et al., “Apelin/APJ axis improves angiotensin II-induced endothelial cell senescence through AMPK/SIRT1 signaling pathway,” Archives of Medical Science, vol. 14, no. 4, pp. 725–734, 2018.
View at: Publisher Site | Google Scholar
Z. Z. Zhang, W. Wang, H. Y. Jin et al., “Apelin is a negative regulator of angiotensin II-mediated adverse myocardial remodeling and dysfunction,” Hypertension, vol. 70, no. 6, pp. 1165–1175, 2017.
View at: Publisher Site | Google Scholar
M. Tang, Z. Huang, X. Luo et al., “Ferritinophagy activation and sideroflexin1-dependent mitochondria iron overload is involved in apelin-13-induced cardiomyocytes hypertrophy,” Free Radical Biology and Medicine, vol. 134, pp. 445–457, 2019.
View at: Publisher Site | Google Scholar
S. Niknazar, H. A. Abbaszadeh, H. Peyvandi et al., “Protective effect of [Pyr1]-apelin-13 on oxidative stress-induced apoptosis in hair cell-like cells derived from bone marrow mesenchymal stem cells,” European Journal of Pharmacology, vol. 853, pp. 25–32, 2019.
View at: Publisher Site | Google Scholar
H. Zhang, S. Chen, M. Zeng et al., “Apelin-13 administration protects against LPS-induced acute lung injury by inhibiting NF-κB pathway and NLRP3 inflammasome activation,” Cellular Physiology and Biochemistry, vol. 49, no. 5, pp. 1918–1932, 2018.
View at: Publisher Site | Google Scholar
Y. Chi, J. Chai, C. Xu, H. Luo, and Q. Zhang, “Apelin inhibits the activation of the nucleotide-binding domain and the leucine-rich, repeat-containing family, pyrin-containing 3 (NLRP3) inflammasome and ameliorates insulin resistance in severely burned rats,” Surgery, vol. 157, no. 6, pp. 1142–1152, 2015.
View at: Publisher Site | Google Scholar
M. Liu, H. Li, Q. Zhou et al., “ROS-autophagy pathway mediates monocytes-human umbilical vein endothelial cells adhesion induced by apelin-13,” Journal of Cellular Physiology, vol. 233, no. 10, pp. 6839–6850, 2018.
View at: Publisher Site | Google Scholar
T. Xu, J. Jia, N. Xu et al., “Apelin receptor upregulation in spontaneously hypertensive rat contributes to the enhanced vascular smooth muscle cell proliferation by activating autophagy,” Annals of Translational Medicine, vol. 9, no. 8, p. 627, 2021.
View at: Publisher Site | Google Scholar
S. Aminyavari, M. Zahmatkesh, M. Farahmandfar, F. Khodagholi, L. Dargahi, and M. R. Zarrindast, “Protective role of apelin-13 on amyloid beta25-35-induced memory deficit; involvement of autophagy and apoptosis process,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 89, pp. 322–334, 2019.
View at: Publisher Site | Google Scholar
J. Hou, T. Zhong, T. Guo et al., “Apelin promotes mesenchymal stem cells survival and vascularization under hypoxic-ischemic condition in vitro involving the upregulation of vascular endothelial growth factor,” Experimental and Molecular Pathology, vol. 102, no. 2, pp. 203–209, 2017.
View at: Publisher Site | Google Scholar
P. Zhang, A. P. Wang, H. P. Yang et al., “Apelin-13 attenuates high glucose-induced calcification of MOVAS cells by regulating MAPKs and PI3K/AKT pathways and ROS-mediated signals,” Biomedicine & Pharmacotherapy, vol. 128, p. 110271, 2020.
View at: Publisher Site | Google Scholar
K. Chen, X. L. Zhao, L. B. Li et al., “miR-503/apelin-12 mediates high glucose-induced microvascular endothelial cells injury via JNK and p38MAPK signaling pathway,” Regenerative Therapy, vol. 14, pp. 111–118, 2020.
View at: Publisher Site | Google Scholar
R. Rai, A. K. Ghosh, M. Eren et al., “Downregulation of the apelinergic axis accelerates aging, whereas its systemic restoration improves the mammalian healthspan,” Cell Reports, vol. 21, no. 6, pp. 1471–1480, 2017.
View at: Publisher Site | Google Scholar
K. Kuba, L. Zhang, Y. Imai et al., “Impaired heart contractility in apelin gene-deficient mice associated with aging and pressure overload,” Circulation Research, vol. 101, no. 4, pp. e32–e42, 2007.
View at: Publisher Site | Google Scholar
W. Wang, M. Shen, C. Fischer et al., “Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs,” Proceedings of the National Academy of Sciences, vol. 116, no. 26, pp. 13006–13015, 2019.
View at: Publisher Site | Google Scholar
W. Jiang, W. Hu, L. Ye et al., “Contribution of apelin-17 to collateral circulation following cerebral ischemic stroke,” Translational Stroke Research, vol. 10, no. 3, pp. 298–307, 2019.
View at: Publisher Site | Google Scholar
Y. Li, Y. Li, Y. Li et al., “Inhibition of endoplasmic reticulum stress mediates the ameliorative effect of apelin on vascular calcification,” Journal of Molecular and Cellular Cardiology, vol. 152, pp. 17–28, 2021.
View at: Publisher Site | Google Scholar
M. R. Izadi, A. Ghardashi Afousi, M. Asvadi Fard, and M. A. Babaee Bigi, “High-intensity interval training lowers blood pressure and improves apelin and NOx plasma levels in older treated hypertensive individuals,” Journal of Physiology and Biochemistry, vol. 74, no. 1, pp. 47–55, 2018.
View at: Publisher Site | Google Scholar
A. G. Japp, N. L. Cruden, G. Barnes et al., “Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure,” Circulation, vol. 121, no. 16, pp. 1818–1827, 2010.
View at: Publisher Site | Google Scholar
G. D. Barnes, S. Alam, G. Carter et al., “Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure,” Circulation: Heart Failure, vol. 6, no. 3, pp. 482–491, 2013.
View at: Publisher Site | Google Scholar
F. A. Russell, R. King, S. J. Smillie, X. Kodji, and S. D. Brain, “Calcitonin gene-related peptide: physiology and pathophysiology,” Physiological Reviews, vol. 94, no. 4, pp. 1099–1142, 2014.
View at: Publisher Site | Google Scholar
Y. Guo, Q. Zhang, H. Chen, Y. Jiang, and P. Gong, “The protective role of calcitonin gene-related peptide (CGRP) in high-glucose- induced oxidative injury in rat aorta endothelial cells,” Peptides, vol. 121, p. 170121, 2019.
View at: Publisher Site | Google Scholar
H. M. Luo, X. Wu, X. Xian et al., “Calcitonin gene-related peptide inhibits angiotensin II-induced NADPH oxidase-dependent ROS via the Src/STAT3 signalling pathway,” Journal of Cellular and Molecular Medicine, vol. 24, no. 11, pp. 6426–6437, 2020.
View at: Publisher Site | Google Scholar
H. M. Luo, X. Wu, W. X. Liu et al., “Calcitonin gene-related peptide attenuates angiotensin II-induced ROS-dependent apoptosis in vascular smooth muscle cells by inhibiting the CaMKII/CREB signalling pathway,” Biochemical and Biophysical Research Communications, vol. 521, no. 2, pp. 285–289, 2020.
View at: Publisher Site | Google Scholar
S. Y. Zeng, L. Yang, C. L. Hong et al., “Evidence that ADAM17 mediates the protective action of CGRP against angiotensin II-induced inflammation in vascular smooth muscle cells,” Mediators of Inflammation, vol. 2018, Article ID 2109352, 10 pages, 2018.
View at: Publisher Site | Google Scholar
P. R. Gangula, M. Chauhan, L. Reed, and C. Yallampalli, “Age-related changes in dorsal root ganglia, circulating and vascular calcitonin gene-related peptide (CGRP) concentrations in female rats: effect of female sex steroid hormones,” Neuroscience Letters, vol. 454, no. 2, pp. 118–123, 2009.
View at: Publisher Site | Google Scholar
R. Lu, H. Q. Zhu, J. Peng, N. S. Li, and Y. J. Li, “Endothelium-dependent vasorelaxation and the expression of calcitonin gene- related peptide in aged rats,” Neuropeptides, vol. 36, no. 6, pp. 407–412, 2002.
View at: Publisher Site | Google Scholar
F. Argunhan, D. Thapa, A. A. Aubdool et al., “Calcitonin gene-related peptide protects against cardiovascular dysfunction independently of nitric oxide in vivo,” Hypertension, vol. 77, no. 4, pp. 1178–1190, 2021.
View at: Publisher Site | Google Scholar
A. D. Struthers, M. J. Brown, D. W. Macdonald et al., “Human calcitonin gene related peptide: a potent endogenous vasodilator in man,” Clinical Science, vol. 70, no. 4, pp. 389–393, 1986.
View at: Publisher Site | Google Scholar
Y. C. Shekhar, I. S. Anand, R. Sarma, R. Ferrari, P. L. Wahi, and P. A. Poole-Wilson, “Effects of prolonged infusion of human alpha calcitonin gene-related peptide on hemodynamics, renal blood flow and hormone levels in congestive heart failure,” The American Journal of Cardiology, vol. 67, no. 8, pp. 732–736, 1991.
View at: Publisher Site | Google Scholar
L. A. Calo, L. Dal Maso, E. Pagnin et al., “Effect of olmesartan medoxomil on number and survival of circulating endothelial progenitor cells and calcitonin gene related peptide in hypertensive patients,” Journal of Hypertension, vol. 32, no. 1, pp. 193–199, 2014.
View at: Publisher Site | Google Scholar
A. A. Voors, D. Kremer, C. Geven et al., “Adrenomedullin in heart failure: pathophysiology and therapeutic application,” European Journal of Heart Failure, vol. 21, no. 2, pp. 163–171, 2019.
View at: Publisher Site | Google Scholar
T. Shindo, Y. Kurihara, H. Nishimatsu et al., “Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene,” Circulation, vol. 104, no. 16, pp. 1964–1971, 2001.
View at: Publisher Site | Google Scholar
A. Iring, Y. J. Jin, J. Albarran-Juarez et al., “Shear stress-induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure,” The Journal of Clinical Investigation, vol. 129, no. 7, pp. 2775–2791, 2019.
View at: Publisher Site | Google Scholar
T. Koyama, L. Ochoa-Callejero, T. Sakurai et al., “Vascular endothelial adrenomedullin-RAMP2 system is essential for vascular integrity and organ homeostasis,” Circulation, vol. 127, no. 7, pp. 842–853, 2013.
View at: Publisher Site | Google Scholar
X. Xian, T. Sakurai, A. Kamiyoshi et al., “Vasoprotective activities of the adrenomedullin-RAMP2 system in endothelial cells,” Endocrinology, vol. 158, no. 5, pp. 1359–1372, 2017.
View at: Publisher Site | Google Scholar
Y. Mitome-Mishima, N. Miyamoto, R. Tanaka et al., “Adrenomedullin deficiency and aging exacerbate ischemic white matter injury after prolonged cerebral hypoperfusion in mice,” BioMed Research International, vol. 2014, Article ID 861632, 13 pages, 2014.
View at: Publisher Site | Google Scholar
K. Igarashi, T. Sakurai, A. Kamiyoshi et al., “Pathophysiological roles of adrenomedullin-RAMP2 system in acute and chronic cerebral ischemia,” Peptides, vol. 62, pp. 21–31, 2014.
View at: Publisher Site | Google Scholar
T. Nishikimi, T. Karasawa, C. Inaba et al., “Effects of long-term intravenous administration of adrenomedullin (AM) plus hANP therapy in acute decompensated heart failure: a pilot study,” Circulation Journal, vol. 73, no. 5, pp. 892–898, 2009.
View at: Publisher Site | Google Scholar
N. Nagaya, T. Satoh, T. Nishikimi et al., “Hemodynamic, renal, and hormonal effects of adrenomedullin infusion in patients with congestive heart failure,” Circulation, vol. 101, no. 5, pp. 498–503, 2000.
View at: Publisher Site | Google Scholar
J. Kato, K. Kitamura, T. Uemura et al., “Plasma levels of adrenomedullin and atrial and brain natriuretic peptides in the general population: their relations to age and pulse pressure,” Hypertension Research, vol. 25, no. 6, pp. 887–892, 2002.
View at: Publisher Site | Google Scholar
X. Q. Ni, J. S. Zhang, C. S. Tang, and Y. F. Qi, “Intermedin/adrenomedullin2: an autocrine/paracrine factor in vascular homeostasis and disease,” Science China Life Sciences, vol. 57, no. 8, pp. 781–789, 2014.
View at: Publisher Site | Google Scholar
S. Y. Zhang, M. J. Xu, and X. Wang, “Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases,” British Journal of Pharmacology, vol. 175, no. 8, pp. 1230–1240, 2018.
View at: Publisher Site | Google Scholar
Y. Chen, L. S. Zhang, J. L. Ren et al., “Intermedin1-53 attenuates aging-associated vascular calcification in rats by upregulating sirtuin 1,” Aging (Albany NY), vol. 12, no. 7, pp. 5651–5674, 2020.
View at: Publisher Site | Google Scholar
J. R. Chang, J. Guo, Y. Wang et al., “Intermedin_1-53 attenuates vascular calcification in rats with chronic kidney disease by upregulation of α-Klotho,” Kidney International, vol. 89, no. 3, pp. 586–600, 2016.
View at: Publisher Site | Google Scholar
J. L. Ren, Y. Chen, L. S. Zhang et al., “Intermedin_1-53 attenuates atherosclerotic plaque vulnerability by inhibiting CHOP-mediated apoptosis and inflammasome in macrophages,” Cell Death & Disease, vol. 12, no. 5, pp. 1–16, 2021.
View at: Publisher Site | Google Scholar
J. L. Ren, Y. L. Hou, X. Q. Ni et al., “Intermedin1-53 ameliorates homocysteine-promoted atherosclerotic calcification by inhibiting endoplasmic reticulum stress,” Journal of Cardiovascular Pharmacology and Therapeutics, vol. 25, no. 3, pp. 251–264, 2020.
View at: Google Scholar
W. W. Lu, L. X. Jia, X. Q. Ni et al., “Intermedin1-53 attenuates abdominal aortic aneurysm by inhibiting oxidative stress,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 36, no. 11, pp. 2176–2190, 2016.
View at: Publisher Site | Google Scholar
X. Q. Ni, Y. R. Zhang, L. X. Jia et al., “Inhibition of Notch1-mediated inflammation by intermedin protects against abdominal aortic aneurysm via PI3K/Akt signaling pathway,” Aging (Albany NY), vol. 13, no. 4, pp. 5164–5184, 2021.
View at: Publisher Site | Google Scholar
J. D. Li, W. S. An, Y. Xu et al., “Mechanism of vasoactive peptide intermedin in vascular collagen remodeling during angiotensin II-induced hypertention,” European Review for Medical and Pharmacological Sciences, vol. 22, no. 17, pp. 5652–5658, 2018.
View at: Publisher Site | Google Scholar
A. J. Moyes and A. J. Hobbs, “C-type natriuretic peptide: a multifaceted paracrine regulator in the heart and vasculature,” International Journal of Molecular Sciences, vol. 20, no. 9, p. 2281, 2019.
View at: Publisher Site | Google Scholar
A. J. Moyes, R. S. Khambata, I. Villar et al., “Endothelial C-type natriuretic peptide maintains vascular homeostasis,” The Journal of Clinical Investigation, vol. 124, no. 9, pp. 4039–4051, 2014.
View at: Publisher Site | Google Scholar
W. Chen, F. Werner, A. Illerhaus et al., “Stabilization of perivascular mast cells by endothelial CNP (C-type natriuretic peptide),” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 40, no. 3, pp. 682–696, 2020.
View at: Publisher Site | Google Scholar
K. J. Bubb, A. A. Aubdool, A. J. Moyes et al., “Endothelial C-type natriuretic peptide is a critical regulator of angiogenesis and vascular remodeling,” Circulation, vol. 139, no. 13, pp. 1612–1628, 2019.
View at: Publisher Site | Google Scholar
K. Špiranec, W. Chen, F. Werner et al., “Endothelial C-type natriuretic peptide acts on pericytes to regulate microcirculatory flow and blood pressure,” Circulation, vol. 138, no. 5, pp. 494–508, 2018.
View at: Publisher Site | Google Scholar
K. Nakao, K. Kuwahara, T. Nishikimi et al., “Endothelium-derived C-type natriuretic peptide contributes to blood pressure regulation by maintaining endothelial integrity,” Hypertension, vol. 69, no. 2, pp. 286–296, 2017.
View at: Publisher Site | Google Scholar
C. Caniffi, F. M. Cerniello, G. Bouchet et al., “Chronic treatment with C-type natriuretic peptide impacts differently in the aorta of normotensive and hypertensive rats,” Pflügers Archiv-European Journal of Physiology, vol. 471, no. 8, pp. 1103–1115, 2019.
View at: Publisher Site | Google Scholar
J. J. Chen, J. Zhang, Y. Cai et al., “C-type natriuretic peptide inhibiting vascular calcification might involve decreasing bone morphogenic protein 2 and osteopontin levels,” Molecular and Cellular Biochemistry, vol. 392, no. 1-2, pp. 65–76, 2014.
View at: Publisher Site | Google Scholar
S. Del Ry, M. Cabiati, T. Stefano et al., “Comparison of NT-proCNP and CNP plasma levels in heart failure, diabetes and cirrhosis patients,” Regulatory Peptides, vol. 166, no. 1-3, pp. 15–20, 2011.
View at: Publisher Site | Google Scholar
D. J. Lok, I. T. Klip, A. A. Voors et al., “Prognostic value of N-terminal pro C-type natriuretic peptide in heart failure patients with preserved and reduced ejection fraction,” European Journal of Heart Failure, vol. 16, no. 9, pp. 958–966, 2014.
View at: Publisher Site | Google Scholar
T. C. Prickett, R. N. Doughty, R. W. Troughton et al., “C-Type natriuretic peptides in coronary disease,” Clinical Chemistry, vol. 63, no. 1, pp. 316–324, 2017.
View at: Publisher Site | Google Scholar
S. J. Sangaralingham, P. M. McKie, T. Ichiki et al., “Circulating C-type natriuretic peptide and its relationship to cardiovascular disease in the general population,” Hypertension, vol. 65, no. 6, pp. 1187–1194, 2015.
View at: Publisher Site | Google Scholar
J. Liang, Y. Bai, W. Chen, Y. Fu, Y. Liu, and X. Yin, “Cortistatin, a novel cardiovascular protective peptide,” Cardiovascular Diagnosis and Therapy, vol. 9, no. 4, pp. 394–399, 2019.
View at: Publisher Site | Google Scholar
Y. Liu, F. Lin, Y. Fu et al., “Cortistatin inhibits calcification of vascular smooth muscle cells by depressing osteoblastic differentiation and endoplasmic reticulum stress,” Amino Acids, vol. 48, no. 11, pp. 2671–2681, 2016.
View at: Publisher Site | Google Scholar
Y. Liu, F. Lin, Y. Fu et al., “Cortistatin inhibits arterial calcification in rats via GSK3β/β-catenin and protein kinase C signalling but not c-Jun N-terminal kinase signalling,” Acta Physiologica, vol. 223, no. 3, p. e13055, 2018.
View at: Publisher Site | Google Scholar
Y. Wang, X. Zhang, W. Chen et al., “Cortistatin ameliorates Ang II-induced proliferation of vascular smooth muscle cells by inhibiting autophagy through SSTR3 and SSTR5,” Life Sciences, vol. 253, p. 117726, 2020.
View at: Publisher Site | Google Scholar
Y. Wang, X. Zhang, L. Gao et al., “Cortistatin exerts antiproliferation and antimigration effects in vascular smooth muscle cells stimulated by Ang II through suppressing ERK1/2, p38 MAPK, JNK and ERK5 signaling pathways,” Annals of Translational Medicine, vol. 7, no. 20, p. 561, 2019.
View at: Publisher Site | Google Scholar
M. Duran-Prado, M. Morell, V. Delgado-Maroto et al., “Cortistatin inhibits migration and proliferation of human vascular smooth muscle cells and decreases neointimal formation on carotid artery ligation,” Circulation Research, vol. 112, no. 11, pp. 1444–1455, 2013.
View at: Publisher Site | Google Scholar
Y. Liu, Y. B. Zhou, G. G. Zhang et al., “Cortistatin attenuates vascular calcification in rats,” Regulatory Peptides, vol. 159, no. 1-3, pp. 35–43, 2010.
View at: Publisher Site | Google Scholar
V. Delgado-Maroto, R. Benitez, I. Forte-Lago et al., “Cortistatin reduces atherosclerosis in hyperlipidemic ApoE-deficient mice and the formation of foam cells,” Scientific Reports, vol. 7, no. 1, p. 46444, 2017.
View at: Publisher Site | Google Scholar
H. Chai, Z. Tao, W. Chen et al., “Cortistatin attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of the ERK1/2 signaling pathways,” Biochemical and Biophysical Research Communications, vol. 495, no. 2, pp. 1801–1806, 2018.
View at: Publisher Site | Google Scholar
Y. Yin and W. Zhang, “The role of ghrelin in senescence: a mini-review,” Gerontology, vol. 62, no. 2, pp. 155–162, 2016.
View at: Publisher Site | Google Scholar
J. T. Pearson, M. Shirai, V. Sukumaran et al., “Ghrelin and vascular protection,” Vascular Biology, vol. 1, no. 1, pp. H97–H102, 2019.
View at: Publisher Site | Google Scholar
N. Fujitsuka, A. Asakawa, A. Morinaga et al., “Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1,” Molecular Psychiatry, vol. 21, no. 11, pp. 1613–1623, 2016.
View at: Publisher Site | Google Scholar
G. Togliatto, A. Trombetta, P. Dentelli et al., “Unacylated ghrelin induces oxidative stress resistance in a glucose intolerance and peripheral artery disease mouse model by restoring endothelial cell miR-126 expression,” Diabetes, vol. 64, no. 4, pp. 1370–1382, 2015.
View at: Publisher Site | Google Scholar
S. Xu, F. Ye, L. Li et al., “Ghrelin attenuates vascular calcification in diabetic patients with amputation,” Biomedicine & Pharmacotherapy, vol. 91, pp. 1053–1064, 2017.
View at: Publisher Site | Google Scholar
M. Xu, L. Liu, C. Song, W. Chen, and S. Gui, “Ghrelin improves vascular autophagy in rats with vascular calcification,” Life Sciences, vol. 179, pp. 23–29, 2017.
View at: Publisher Site | Google Scholar
M. Zanetti, G. Gortan Cappellari, A. Graziani, and R. Barazzoni, “Unacylated ghrelin improves vascular dysfunction and attenuates atherosclerosis during high-fat diet consumption in rodents,” International Journal of Molecular Sciences, vol. 20, no. 3, p. 499, 2019.
View at: Publisher Site | Google Scholar
L. Wang, Q. Chen, D. Ke, and G. Li, “Ghrelin inhibits atherosclerotic plaque angiogenesis and promotes plaque stability in a rabbit atherosclerotic model,” Peptides, vol. 90, pp. 17–26, 2017.
View at: Publisher Site | Google Scholar
M. Zanetti, G. Gortan Cappellari, A. Semolic et al., “Gender-specific association of desacylated ghrelin with subclinical atherosclerosis in the metabolic syndrome,” Archives of Medical Research, vol. 48, no. 5, pp. 441–448, 2017.
View at: Publisher Site | Google Scholar
A. Virdis, E. Duranti, R. Colucci et al., “Ghrelin restores nitric oxide availability in resistance circulation of essential hypertensive patients: role of NAD(P)H oxidase,” European Heart Journal, vol. 36, no. 43, pp. 3023–3030, 2015.
View at: Publisher Site | Google Scholar
C. Graaf, D. Donnelly, D. Wootten et al., “Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes,” Pharmacological Reviews, vol. 68, no. 4, pp. 954–1013, 2016.
View at: Publisher Site | Google Scholar
M. Almutairi, R. Al Batran, and J. R. Ussher, “Glucagon-like peptide-1 receptor action in the vasculature,” Peptides, vol. 111, pp. 26–32, 2019.
View at: Publisher Site | Google Scholar
J. Lonborg, H. Kelbaek, N. Vejlstrup et al., “Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia,” Circulation: Cardiovascular Interventions, vol. 5, no. 2, pp. 288–295, 2012.
View at: Publisher Site | Google Scholar
K. Taguchi, N. Bessho, N. Kaneko, K. Okudaira, T. Matsumoto, and T. Kobayashi, “Glucagon-like peptide-1 increased the vascular relaxation response via AMPK/Akt signaling in diabetic mice aortas,” European Journal of Pharmacology, vol. 865, p. 172776, 2019.
View at: Publisher Site | Google Scholar
S. Misuth, M. Uhrinova, J. Klimas, D. Vavrincova-Yaghi, and P. Vavrinec, “Vildagliptin improves vascular smooth muscle relaxation and decreases cellular senescence in the aorta of doxorubicin-treated rats,” Vascular Pharmacology, vol. 138, p. 106855, 2021.
View at: Publisher Site | Google Scholar
S. H. Fan, Q. F. Xiong, L. Wang, L. H. Zhang, and Y. W. Shi, “Glucagon-like peptide 1 treatment reverses vascular remodelling by downregulating matrix metalloproteinase 1 expression through inhibition of the ERK1/2/NF-kappaB signalling pathway,” Molecular and Cellular Endocrinology, vol. 518, p. 111005, 2020.
View at: Publisher Site | Google Scholar
P. Altieri, R. Murialdo, C. Barisione et al., “5-fluorouracil causes endothelial cell senescence: potential protective role of glucagon-like peptide 1,” British Journal of Pharmacology, vol. 174, no. 21, pp. 3713–3726, 2017.
View at: Publisher Site | Google Scholar
J. Helmstadter, K. Frenis, K. Filippou et al., “Endothelial GLP-1 (glucagon-like peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 40, no. 1, pp. 145–158, 2020.
View at: Publisher Site | Google Scholar
L. Piao, G. Zhao, E. Zhu et al., “Chronic psychological stress accelerates vascular senescence and impairs ischemia-induced neovascularization: the role of dipeptidyl peptidase-4/glucagon-like peptide-1-adiponectin axis,” Journal of the American Heart Association, vol. 6, no. 10, p. e006421, 2017.
View at: Publisher Site | Google Scholar
L. Zhao, A. Q. Li, T. F. Zhou, M. Q. Zhang, and X. M. Qin, “Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway,” American Journal of Physiology-Cell Physiology, vol. 307, no. 12, pp. C1130–C1141, 2014.
View at: Publisher Site | Google Scholar
T. Zhou, M. Zhang, L. Zhao, A. Li, and X. Qin, “Activation of Nrf2 contributes to the protective effect of Exendin-4 against angiotensin II-induced vascular smooth muscle cell senescence,” American Journal of Physiology-Cell Physiology, vol. 311, no. 4, pp. C572–C582, 2016.
View at: Publisher Site | Google Scholar
W. Chang, F. Zhu, H. Zheng et al., “Glucagon-like peptide-1 receptor agonist dulaglutide prevents ox-LDL-induced adhesion of monocytes to human endothelial cells: An implication in the treatment of atherosclerosis,” Molecular Immunology, vol. 116, pp. 73–79, 2019.
View at: Publisher Site | Google Scholar
S. Nizari, M. Basalay, P. Chapman et al., “Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke,” Basic Research in Cardiology, vol. 116, no. 1, p. 32, 2021.
View at: Publisher Site | Google Scholar
Y. Shan, S. Tan, Y. Lin et al., “The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke,” Journal of Neuroinflammation, vol. 16, no. 1, p. 242, 2019.
View at: Publisher Site | Google Scholar
S. T. Tang, Q. Zhang, H. Q. Tang et al., “Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor κB signaling pathways,” Endocrine, vol. 53, no. 1, pp. 107–116, 2016.
View at: Publisher Site | Google Scholar
M. Wajdlich and M. Nowicki, “Hemodynamic effect of a single dose of glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide in patients with diabetic kidney disease,” Journal of Physiology and Pharmacology: an Official Journal of the Polish Physiological Society, vol. 72, no. 5, 2021.
View at: Publisher Site | Google Scholar
J. Westerink, K. S. Matthiessen, S. Nuhoho et al., “Estimated life-years gained free of new or recurrent major cardiovascular events with the addition of semaglutide to standard of care in people with type 2 diabetes and high cardiovascular risk,” Diabetes Care, vol. 45, no. 5, pp. 1211–1218, 2022.
View at: Publisher Site | Google Scholar
F. Chen, L. He, J. Li et al., “Polyethylene glycol loxenatide injection (GLP-1) protects vascular endothelial cell function in middle-aged and elderly patients with type 2 diabetes by regulating gut microbiota,” Frontiers in Molecular Biosciences, vol. 9, p. 879294, 2022.
View at: Publisher Site | Google Scholar
Y. Hashimoto, T. Niikura, H. Tajima et al., “A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta,” Proceedings of the National Academy of Sciences, vol. 98, no. 11, pp. 6336–6341, 2001.
View at: Publisher Site | Google Scholar
L. Rochette, A. Meloux, M. Zeller, Y. Cottin, and C. Vergely, “Role of humanin, a mitochondrial-derived peptide, in cardiovascular disorders,” Archives of Cardiovascular Diseases, vol. 113, no. 8-9, pp. 564–571, 2020.
View at: Publisher Site | Google Scholar
A. R. Bachar, L. Scheffer, A. S. Schroeder et al., “Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress,” Cardiovascular Research, vol. 88, no. 2, pp. 360–366, 2010.
View at: Publisher Site | Google Scholar
Y. K. Oh, A. R. Bachar, D. G. Zacharias et al., “Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice,” Atherosclerosis, vol. 219, no. 1, pp. 65–73, 2011.
View at: Publisher Site | Google Scholar
X. Wang, Z. Wu, Y. He et al., “Humanin prevents high glucose-induced monocyte adhesion to endothelial cells by targeting KLF2,” Molecular Immunology, vol. 101, pp. 245–250, 2018.
View at: Publisher Site | Google Scholar
W. Li, D. Zhang, W. Yuan, C. Wang, Q. Huang, and J. Luo, “Humanin ameliorates free fatty acid-induced endothelial inflammation by suppressing the NLRP3 inflammasome,” ACS Omega, vol. 5, no. 35, pp. 22039–22045, 2020.
View at: Publisher Site | Google Scholar
Y. Ding, Y. Feng, W. Zhu et al., “[Gly14]-Humanin prevents lipid deposition and endothelial cell apoptosis in a lectin-like oxidized low-density lipoprotein receptor-1-dependent manner,” Lipids, vol. 54, no. 11-12, pp. 697–705, 2019.
View at: Publisher Site | Google Scholar
Y. Ding, Y. Feng, Y. Zou et al., “[Gly14]-humanin restores cathepsin D function via FPRL1 and promotes autophagic degradation of Ox-LDL in HUVECs,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 30, no. 12, pp. 2406–2416, 2020.
View at: Publisher Site | Google Scholar
T. Peng, W. Wan, J. Wang et al., “The neurovascular protective effect of S14G-humanin in a murine MCAO model and brain endothelial cells,” IUBMB Life, vol. 70, no. 7, pp. 691–699, 2018.
View at: Publisher Site | Google Scholar
S. S. Jung and W. E. V. Nostrand, “Humanin rescues human cerebrovascular smooth muscle cells from Abeta-induced toxicity,” Journal of Neurochemistry, vol. 84, no. 2, pp. 266–272, 2003.
View at: Publisher Site | Google Scholar
X. Zhang, V. H. Urbieta-Caceres, A. Eirin et al., “Humanin prevents intra-renal microvascular remodeling and inflammation in hypercholesterolemic ApoE deficient mice,” Life Sciiences, vol. 91, no. 5-6, pp. 199–206, 2012.
View at: Publisher Site | Google Scholar
R. J. Widmer, A. J. Flammer, J. Herrmann et al., “Circulating humanin levels are associated with preserved coronary endothelial function,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 304, no. 3, pp. H393–H397, 2013.
View at: Publisher Site | Google Scholar
Y. Xu, Q. Wang, Z. Qu, J. Yang, X. Zhang, and Y. Zhao, “Protective effect of hyperbaric oxygen therapy on cognitive function in patients with vascular dementia,” Cell Transplantation, vol. 28, no. 8, pp. 1071–1075, 2019.
View at: Publisher Site | Google Scholar
R. H. Muzumdar, D. M. Huffman, G. Atzmon et al., “Humanin: a novel central regulator of peripheral insulin action,” PLoS One, vol. 4, no. 7, p. e6334, 2009.
View at: Publisher Site | Google Scholar
M. Conte, R. Ostan, C. Fabbri et al., “Human aging and longevity are characterized by high levels of mitokines,” The Journals of Gerontology: Series A, vol. 74, no. 5, pp. 600–607, 2019.
View at: Publisher Site | Google Scholar

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Oxidative Medicine and Cellular Longevity

Endogenous Vasoactive Peptides and Vascular Aging-Related Diseases

Abstract

1. Introduction

2. Vascular Aging and Vascular Aging-Related Diseases

3. Vasoactive Peptides and Vascular Aging-Related Diseases

3.1. Angiotensin 1-7 (Ang-(1-7))

3.2. Apelin

3.3. Calcitonin Gene-Related Peptide (CGRP) Family

3.3.1. CGRP

3.3.2. Adrenomedullin (AM)

3.3.3. Intermedin (IMD)

3.4. C-Type Natriuretic Peptide (CNP)

3.5. Cortistatin (CST)

3.6. Ghrelin

3.7. Glucagon-Like Peptide-1 (GLP-1)

3.8. Humanin (HN)

4. Endogenous Vasoactive Peptide-Based Diagnostic Tools and Intervention Measures in Vascular Aging-Related Diseases

5. Conclusions

6. Future Research Directions

Data Availability

Conflicts of Interest

Acknowledgments

References

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