The Role of Calcitonin Gene Related Peptide (CGRP) in Neurogenic Vasodilation and Its Cardioprotective Effects

Abstract

Calcitonin gene-related peptide (CGRP) is a highly potent vasoactive peptide released from sensory nerves, which is now proposed to have protective effects in several cardiovascular diseases. The major α-form is produced from alternate splicing and processing of the calcitonin gene. The CGRP receptor is a complex composed of calcitonin like receptor (CLR) and a single transmembrane protein, RAMP1. CGRP is a potent vasodilator and proposed to have protective effects in several cardiovascular diseases. CGRP has a proven role in migraine and selective antagonists and antibodies are now reaching the clinic for treatment of migraine. These clinical trials with antagonists and antibodies indicate that CGRP does not play an obvious role in the physiological control of human blood pressure. This review discusses the vasodilator and hypotensive effects of CGRP and the role of CGRP in mediating cardioprotective effects in various cardiovascular models and disorders. In models of hypertension, CGRP protects against the onset and progression of hypertensive states by potentially counteracting against the pro-hypertensive systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic system. With regards to its cardioprotective effects in conditions such as heart failure and ischaemia, CGRP-containing nerves innervate throughout cardiac tissue and the vasculature, where evidence shows this peptide alleviates various aspects of their pathophysiology, including cardiac hypertrophy, reperfusion injury, cardiac inflammation, and apoptosis. Hence, CGRP has been suggested as a cardioprotective, endogenous mediator released under stress to help preserve cardiovascular function. With the recent developments of various CGRP-targeted pharmacotherapies, in the form of CGRP antibodies/antagonists as well as a CGRP analog, this review provides a summary and a discussion of the most recent basic science and clinical findings, initiating a discussion on the future of CGRP as a novel target in various cardiovascular diseases.

Could CGRP Antagonists Be Helpful in the Fight Against COVID‐19?

“…In addition to its location throughout the peripheral sensory and central nervous system, CGRP has been associated with perivascular neurons densely distributed in the myocardium and coronary vessels. 2,3 It is a potent vasoactive peptide and has been suggested to be a cardioprotective mediator in conditions such as heart failure and ischemia. [2][3][4][5] CGRP has also been found in pulmonary afferent nerve fibers and contributes to vasodilation of pulmonary vasculature.…”

“…2,3 It is a potent vasoactive peptide and has been suggested to be a cardioprotective mediator in conditions such as heart failure and ischemia. [2][3][4][5] CGRP has also been found in pulmonary afferent nerve fibers and contributes to vasodilation of pulmonary vasculature. 6 So what effect would exogenously blocking CGRP have on the outcome of acute respiratory failure?…”

“…It is not clear, for example, if temporary blockade of CGRP in these patients might predispose to worsening systemic hypertension, pulmonary hypertension, 5 or ischemic organ injury. 2,4,15 If a CGRP receptor antagonist is ultimately found to be helpful in reducing the severe morbidity and mortality of these critically ill patients, this might inspire numerous additional investigative opportunities. For instance, would CGRP antagonists be more effective if given early and continuously, similar to the ovine model of acute lung injury, or is it more effective as a treatment after some level of respiratory compromise has occurred?…”

Calcitonin Gene-Related Peptide and Substance P As Predictors of Venous Pelvic Pain

“…As proved by earlier studies, there is no obvious relationship between the diameter of pelvic veins and the severity of VPP [14,15]. Meanwhile, the findings obtained by several authors indicate that there might be a relationship between neurogenic inflammation, hyperproduction, and increased activity of vasoactive neuropeptides and the emergence of VPP formation [16,17,18,19].…”

Novel potentials of dipeptidyl peptidase-4 inhibitor sitagliptin against ischemia-reperfusion (I/R) injury in normolipidemic and hyperlipidemic animals

“…The latter functions upon a chemical or physical stimuli like capsaicin, proton and heat, releasing sensory neuropeptides functioning as vasodilators, like calcitonin gene-related peptide (CGRP) and substance P [103], exhibiting cardioprotective effects. CGRP is a neuropeptide that consitutes the sensory nerves and synthesized in the dorsal root ganglia of the sensory nerves that terminates to the cardiovascular system [104], mediating cardioprotection and regulating cardiac function [105], and reduction in capsaicin sensitve neurons reduces myocardial CGRP and impairs cardiac function [106]. CGRP is upstreamly regulated by the TRPV-1 that promotes its release upon stimulation (TRPV-1-CGRP pathway) [107].…”