BPS Bill Bowman Lecture & Burdon Sanderson Cardiac Science Seminar: Dr Aisah Aubdool, William Harvey Research Institute, QMUL - ‘Calcitonin Gene-Related Peptide: A Neuropeptide of Many Talents in the Cardiovascular System"

Sensory nerves contain and release the highly potent vasodilator calcitonin gene-related peptide (CGRP). Whilst blocking the action of CGRP does not influence blood pressure regulation in healthy individuals, deletion or blockade of CGRP activity can worsen cardiovascular diseases in various animal models. Transient receptor potential ankyrin-1 (TRPA1) are non-selective cation channels that are widely expressed on sensory nerves, and using a murine model of local environmental cold exposure, we demonstrated that TRPA1 acts a primary vascular cold sensor. The cold-induced vascular response consists of vasoconstriction followed by vasodilatation. This vasodilator phase is critical for protecting the cutaneous tissues against cold injury. We have now identified that TRPA1 activation is required to initiate the constrictor response as well as the subsequent dilator response, mediated by the sensory nerve-derived dilator CGRP and nitric oxide. This highlights the major involvement of the TRPA1-CGRP dilator pathway in the physiological reflex to local cold exposure, and provides impetus for further research in developing therapeutic agents aimed at protecting the skin in peripheral vascular disease and adverse climates.

However, the influence of the TRPA1-CGRP pathway is less easy to determine systemically in the cardiovascular system. Whilst TRPA1 deletion had no effect on blood pressure changes in hypertension, CGRP deletion led to a worsened hypertensive phenotype. Understanding the extent of the hypotensive properties of CGRP on cardiovascular protection will enable us to develop feasible ways to increase CGRP activity as a potential effective therapy for cardiovascular diseases. Our most recent findings supplemented this hypothesis; using a novel long lasting CGRP analogue in collaboration with Novo Nordisk we demonstrated that chronic treatment with a CGRP agonist protects against hypertension, reducing blood pressure, vascular, renal and cardiac hypertrophy, fibrosis and oxidative stress. These protective effects are consistent with further experiments in a model of heart failure where the CGRP agonist preserves cardiac function, and prevents cardiac remodelling and limits damage associated with the progression of heart failure.

Whilst the activity of TRPA1 to release CGRP from sensory nerves appear to be site and stimulus specific, the role of CGRP, more generally when released endogenously or administered exogenously appears to be pivotal in cardiovascular disease. Our current findings provide evidence for a potential novel therapeutic strategy, with the concept that CGRP agonists are anti-hypertensive and cardioprotective, with limited adverse effects when treatment starts early onset of hypertension or heart failure.