The Neuropeptide alpha-Calcitonin Gene-Related Peptide as the Mediator of Beneficial Effects of Exercise in the Cardiovascular System

Regular physical activity exerts cardiovascular protective effects in healthy individuals and those with chronic cardiovascular diseases. Exercise is accompanied by an increased plasma concentration of alpha-calcitonin gene-related peptide (alpha CGRP), a 37-amino acid peptide with vasodilatory effects and causative roles in migraine. Moreover, mouse models revealed that loss of alpha CGRP disrupts physiological adaptation of the cardiovascular system to exercise in normotension and aggravates cardiovascular impairment in primary chronic hypertension, both can be reversed by alpha CGRP administration. This suggests that alpha CGRP agonists could be a therapeutic option to mediate the cardiovascular protective effects of exercise in clinical setting where exercise is not possible or contraindicated. Of note, FDA has recently approved alpha CGRP antagonists for migraine prophylaxis therapy, however, the cardiovascular safety of long-term anti-CGRP therapy in individuals with cardiovascular diseases has yet to be established. Current evidence from preclinical models suggests that chronic alpha CGRP antagonism may abolish the cardiovascular protective effects of exercise in both normotension and chronic hypertension.