Blood Pressure Normalization-Independent Cardioprotective Effects of Endogenous, Physical Activity-Induced αCGRP (α Calcitonin Gene-Related Peptide) in Chronically Hypertensive Mice

Rationale: alpha CGRP (alpha calcitonin gene-related peptide), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure. Objective: However, we hypothesize that endogenous, physical activity-induced alpha CGRP has blood pressure-independent cardioprotective effects in chronic hypertension. Methods and Results: Chronically hypertensive (one-kidney-one-clip surgery) wild-type and alpha CGRP(-/-) sedentary or voluntary wheel running mice were treated with vehicle, alpha CGRP, or the alpha CGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular, and histological analysis, respectively. Blood pressure was similar among all hypertensive experimental groups. Endogenous alpha CGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive wild-type mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In alpha CGRP(-/-) mice, alpha CGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by alpha CGRP suggests involvement of these cells in alpha CGRP-dependent blunting of pathological cardiac remodeling. Conclusions: Endogenous, physical activity-induced alpha CGRP has blood pressure-independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous alpha CGRP signaling, as currently approved for migraine prophylaxis, could endanger patients with hypertension. VISUAL OVERVIEW: An online visual overview is available for this article.