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Review
. 2022 Feb 25:13:833645.
doi: 10.3389/fphys.2022.833645. eCollection 2022.

The Vascular-Dependent and -Independent Actions of Calcitonin Gene-Related Peptide in Cardiovascular Disease

Fulye Argunhan  1 , Susan D Brain  1
Affiliations
Review

The Vascular-Dependent and -Independent Actions of Calcitonin Gene-Related Peptide in Cardiovascular Disease

Fulye Argunhan et al. Front Physiol. .

Abstract

The treatment of hypertension and heart failure remains a major challenge to healthcare providers. Despite therapeutic advances, heart failure affects more than 26 million people worldwide and is increasing in prevalence due to an ageing population. Similarly, despite an improvement in blood pressure management, largely due to pharmacological interventions, hypertension remains a silent killer. This is in part due to its ability to contribute to heart failure. Development of novel therapies will likely be at the forefront of future cardiovascular studies to address these unmet needs. Calcitonin gene-related peptide (CGRP) is a 37 amino acid potent vasodilator with positive-ionotropic and -chronotropic effects. It has been reported to have beneficial effects in hypertensive and heart failure patients. Interestingly, changes in plasma CGRP concentration in patients after myocardial infarction, heart failure, and in some forms of hypertension, also support a role for CGRP on hemodynamic functions. Rodent studies have played an important role thus far in delineating mechanisms involved in CGRP-induced cardioprotection. However, due to the short plasma half-life of CGRP, these well documented beneficial effects have often proven to be acute and transient. Recent development of longer lasting CGRP agonists may therefore offer a practical solution to investigating CGRP further in cardiovascular disease in vivo. Furthermore, pre-clinical murine studies have hinted at the prospect of cardioprotective mechanisms of CGRP which is independent of its hypotensive effect. Here, we discuss past and present evidence of vascular-dependent and -independent processes by which CGRP could protect the vasculature and myocardium against cardiovascular dysfunction.

Keywords: CGRP; cardiovascular; heart; heart failure; hypertension; mouse; nitric oxide.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Proposed cardioprotective mechanisms of CGRP in the (A) vasculature and (B) myocardium. (A) In the vasculature, CGRP circulating in the blood or released from sensory neurons can bind on to its canonical receptor, the CRLR-RAMP1 complex, expressed in the plasma membrane of vascular smooth muscle and endothelial cells to initiate Gαs-protein signal transduction and subsequently cause relaxation of smooth muscle cells via nitric oxide (NO)-dependent and -independent mechanisms thus leading to vasodilation. (B) In cardiac tissues, there is evidence for CGRP-stimulated modulation of sympathetic outflow and expression of the CRLR-RAMP1 complex on cardiomyocytes. Hence, CGRP has the potential to induce Gαs-protein signaling from sensory and sympathetic nerves leading to increased cardiac contractility, thus positive inotropy and chronotropy. AC, adenyl cyclase; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; GTP, guanosine triphosphate; KATP, ATP-sensitive potassium channels; LTCC, L-type calcium channel; NO, nitric oxide; P, phosphate; PKA, protein kinase A; RyR, ryanodine receptor; sGC, soluble guanylate cyclase. [Images were obtained from smart.servier.com under a Creative Commons Attribution 3.0 Unported License].
See this image and copyright information in PMC

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