Endogenous Vasoactive Peptides and Vascular Aging-Related Diseases

Table 1

Summary of vascular protective effects and underlying mechanisms of some common vasoactive peptides.

Peptides	Receptors	Study sources	Effects and mechanisms	References
Ang-(1-7)	Mas; AT2R	In vitro studies	Anti-EC senescence through activating the cytoprotective Nrf2/HO-1 pathway by enhancing endothelial klotho levels	[30]
			Anti-VSMC senescence through attenuating inflammation by inhibiting NADPH oxidase and NF-κB	[31]
		Animal studies	Vasodilation; (1) Activation of the NO-cGMP-PKG pathway; (2) Counteracted Ang II-induced vasoconstriction-related pathway ERK1/2 via modulation of MKP-1 activity; (3) Increased AT2R/Mas/ACE2 vasodilator axis	[32, 33, 34, 35]
			Protective effects on atherosclerosis; (1) Increased plaque stability by counterregulation of Ang II-induced MMP-8 via p38 MAPK pathway; (2) Reduced atherosclerotic lesions by increasing NO generation	[36, 37]
			Prevented AAAs: inhibited vascular inflammation, extracellular matrix degradation, and VSMC apoptosis via the ERK1/2 signaling pathway	[38]
		Human studies	Increased cerebral blood flow, reduced blood-brain barrier permeability, and inhibited inflammation in the Alzheimer’s disease patients; Preserved the NO generation by increasing telomerase activity in humans with coronary artery disease	[39, 40]
Apelin	APJ	In vitro studies	Anti-EC senescence through reducing ROS production and enhancing telomerase activity by activating AMPK/SIRT1 signaling and through suppressing inflammation and oxidative stress by decreasing JNK and p38 MAPK expression	[45, 56]
			Attenuated VSMC calcification by inhibiting ROS-mediated DNA damage and by regulating MAPKs and PI3K/Akt pathways	[55]
		Animal studies	Antiaging: regulated some senescence-promoting transcription factors such as Sp1, E4F, and GATA4	[57]
			Prevented AAAs: prevented VSMC apoptosis and oxidative stress via upregulation of ACE2	[59]
			Inhibited vascular calcification: prevented ERS activation by stimulating Akt signaling	[61]
		Human studies	Increased cardiac index and collateral circulation and lowered mean arterial pressure and peripheral vascular resistance	[63, 64]
CGRP	CRLR/RAMPs	In vitro studies	Inhibited EC injury by increasing NO production and the eNOS expression and attenuating the oxidative injury by inhibiting NOX4 activation via ERK1/2	[66]
			Inhibited VSMC injury by blocking the CaMKII/CREB signaling pathway, the Src/STAT3 signaling pathway, and the EGFR-ERK1/2 pathway	[67, 68, 69]
		Animal studies	Reduced blood pressure dependently or independently of NO	[70, 71, 72]
		Human studies	Decreased arterial pressure and systemic vascular resistance and improved endothelial function and increased cardiac output in hypertensive and heart failure patients	[73, 74, 75]
AM		Animal studies	Vasodilation: promoted NO formation by activating cAMP/PKA pathway	[77, 78]
			Inhibited vascular injury: inhibited oxidative stress and inflammation and regulated vascular stability and permeability	[79, 80, 81, 82]
		Human studies	Reduced mean arterial pressure and systemic vascular resistance and increased cardiac output in heart failure patients	[83, 84]
IMD		Animal studies	Inhibited vascular calcification: (1) inhibited the osteogenic transdifferentiation of VSMC by upregulating SIRT1 via PI3K/Akt, AMPK, and cAMP/PKA signaling pathways and (2) by upregulating klotho via cAMP/PKA signaling	[88, 89]
			Protective effects on atherosclerosis: inhibited ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation	[90, 91]
			Prevented AAAs; (1) Inhibited inflammation mediated by Notch1 via reducing ADAM10 through PI3K/Akt pathway; (2) Attenuated oxidative stress, inflammation, and VSMC apoptosis by decreasing NOX4 activation	[92, 93]
			Attenuated the vascular collagen remodeling: inhibited phosphorylation of Akt and MAPK	[94]
CNP	NPR-B (GC-B); NPR-C	Animal studies	Inhibited vascular calcification: inhibited the osteogenic transdifferentiation of VSMC by regulating cGMP/PKG pathway	[102]
			Prevented vascular ischemia injury; (1) Prevented perivascular mast cells excessive activation by activating GC-B/cGMP signaling; (2) Exerted proangiogenic effect by activating ERK1/2 and PI3K/Akt via NPR-C	[97, 98]
			Vasodilation; (1) Activated the vascular NO system; (2) Activated GC-B/cGMP signaling; (3) Diminished both profibrotic and proinflammatory cytokines	[96, 99, 100, 101]
		Human studies	CNP level could be a predictor or prognostic marker in vascular ischemia, heart failure, and angina patients	[98, 104, 105, 106]
CST	SSTRs; GHSR1a; MrgX2	In vitro studies	Inhibited VSMC calcification by reducing ERS and inhibited the osteogenic transdifferentiation of VSMC by inhibiting the p-GSK3β/β-catenin signaling pathway and promoting the expression of p-PKC	[108, 10]9
			Ameliorated proliferation and migration of VSMCs by inhibiting autophagy through SSTR3 and SSTR5 and by suppressing the MAPK family pathways, including ERK1/2, p38 MAPK, JNK, and ERK5	[110, 111]
		Animal studies	Inhibited vascular calcification by decreasing Pit1 via GHSR1a	[113]
			Protective effects on atherosclerosis: reduced infiltration of the inflammatory cells in the plaques and enhanced cholesterol efflux from macrophages	[114]
			Prevented AAAs: suppressed apoptosis, inflammation, and oxidative stress by blocking the ERK1/2 signaling pathway	[115]
Ghrelin	GHSR	Animal studies	Antiaging: activated the GHSR-cAMP-CREB-SIRT1 pathway and increased SOD2 expression and decreased ROS level	[118]
			Protective effects on atherosclerosis: decreased the level of proinflammatory cytokines, attenuated oxidative stress, and prevented lipid accumulation	[122, 123]
			Inhibited vascular calcification: attenuated VSMC calcification by improving autophagy through AMPK activation and regulating OPG/RANKL signal	[120, 121]
		Human studies	Increased endogenous antioxidant capacity and restored the NO availability in hypertensive patients; Ghrelin level may be a predictor of vascular calcification and atherosclerosis	[120, 124, 125]
GLP-1	GLP-1R	In vitro studies	Anti-EC injury: prevented oxidative stress, mitochondrial dysfunction, and inflammation via upregulation of KLF2	[137]
			Anti-VSMC senescence; (1) Inhibited Rac1 activation via cAMP/PKA pathway; (2) Increased the acetylation of Nrf2 and the recruitment of CBP to Nrf2	[130, 135, 136]
		Animal studies	Prevented vascular ischemia injury; (1) Decreased inflammation by reducing astrocyte-derived VEGF-A expression through JAK2/STAT3 signaling; (2) Increased cerebral blood flow by a cAMP/PKA signaling pathway; (3) Upregulated the expression of antiaging factors including p-AMPKα, PPAR-γ, PGC-1α, and SIRT1; (4) Promoted angiogenic and vasculogenic actions via the upregulation of adiponectin/AdopR1 signaling through PPAR-γ/PGC-1α activation	[138, 139, 134]
			Improved endothelial function: inhibited inflammation via RAGE/RhoA/ROCK and AMPK mediated NF-κB signaling pathways	[140]
			Vasodilation; (1) Increased NO production by activating the AMPK/Akt pathway; (2) Suppressed vascular remodeling by downregulating MMP1 through inhibition of the ERK1/2-NF-κB signaling pathway; (3) Attenuated vascular fibrosis, inflammation, oxidative stress, and endothelial dysfunction	[129, 131, 133]
		Human studies	Decreased systemic vascular resistance and exerted vasodilatory effect, improved vascular endothelial function, downregulated inflammation-related markers, and decreased cardiovascular disease risk in diabetic patient	[141, 142, 143]
HN	CNTFR/WSX-1/gp130 or FPRL1	In vitro studies	Anti-EC injury; (1) Inhibited inflammation by reducing NLRP3 inflammasome via AMPK pathway and by blocking the NF-κB pathway; (2) Suppressed oxidative stress by downregulating the expression of NOX2; (3) Rescued the expression of the cytoprotective factor KLF2 and its target gene eNOS; (4) Repaired autophagic damage	[146, 147, 148, 149, 150, 151, 152]
		Animal studies	Prevented vascular injury: suppressed apoptosis, inflammation, oxidative stress, and increased eNOS expression	[147, 152, 154]
		Human studies	Improved coronary blood flow and cognitive function in patients with vascular dementia	[155, 156]

AAAs: abdominal aortic aneurysms; ACE2: angiotensin-converting enzyme 2; ADAM: a disintegrin and metalloproteinase domain-containing protein; ADMA: asymmetric dimethylarginine; Akt: protein kinase B; AM: adrenomedullin; AMPK: AMP-activated protein kinase; Ang: angiotensin; APJ: apelin receptor; AT2R: angiotensin type 2 receptor; CaMKII: calcium/calmodulin-dependent protein kinase II; cAMP: cyclic adenosine monophosphate; CBP: CREB binding protein; cGMP: cyclic guanosine monophosphate; CGRP: calcitonin gene-related peptide; CHOP: C/EBP-homologous protein; CNP: C-type natriuretic peptide; CNTFR: ciliary neurotrophic factor receptor; CREB: cAMP-responsive element-binding protein; CRLR: calcitonin receptor-like receptor; CST: cortistatin; EC: endothelial cell; EGFR: epidermal growth factor receptor; ERK: extracellular regulated protein kinases; ERS: endoplasmic reticulum stress; eNOS: endogenous nitric oxide synthase; FPRL1: formyl peptide receptor-like 1; GC-B: guanylate cyclase B; GHSR: growth hormone secretagogue receptor; GLP-1: glucagon-like peptide-1; gp130: glycoprotein 130; GSK3β: glycogen synthase kinase 3β; HN: humanin; HO-1: heme oxygenase-1; HUVEC: human umbilical vein endothelial cell; IMD: intermedin; JAK2: Janus kinase 2; JNK: C-jun kinase enzyme; KLF2: Krüppel-like factor 2; MAPK: mitogen-activated protein kinase; MKP-1: mitogen-activated protein kinase phosphatase-1; MMP: matrix metalloproteinase; MrgX2: Mas-related gene X-2 receptor; NADPH: nicotinamide adenine dinucleotide phosphate; NF-κB: nuclear factor kappa-B; NLRP3: NOD-like receptor family pyrin domain containing 3; NO: nitric oxide; NOx: nitrite/nitrate; NOX4: NADPH oxidase enzyme 4; NPR: natriuretic peptide receptor; Nrf2: nuclear factor-erythroid 2-related factor 2; OPG: osteoprotegerin; PGC-1α: PPAR-γ coactivator-1α; PI3K: phosphatidylinositol 3 kinase; PKA: protein kinase A; PKC: protein kinase C; PKG: protein kinase G; PPAR-γ: peroxisome proliferator-activated receptors-γ; RAGE: receptor for advanced glycation end products; RAMP: receptor activity-modifying protein; RANKL: receptor activator of nuclear factor kappa B ligand; ROCK: Rho associated coiled coil forming protein kinase; ROS: reactive oxygen species; SIRT1: sirtuin1; SSTR: somatostatin receptor; STAT3: signal transducers and activators of transduction-3; TNF-α: tumor necrosis factor-α; VEGF-A: vascular endothelial growth factor-A; VSMC: vascular smooth muscle cell.