Receptor Activity-Modifying Protein-1 Augments Cerebrovascular Responses to Calcitonin Gene-Related Peptide and Inhibits Angiotensin II-Induced Vascular Dysfunction

Background and Purpose-Receptors for calcitonin gene-related peptide (CGRP) are composed of the calcitonin-like receptor in association with receptor activity-modifying protein-1 (RAMP1). CGRP is an extremely potent vasodilator and may protect against vascular disease through other mechanisms. Methods-We tested the hypothesis that overexpression of RAMP1 enhances vascular effects of CGRP using transgenic mice with ubiquitous expression of human RAMP1. Because angiotensin II (Ang II) is a key mediator of vascular disease, we also tested the hypothesis that RAMP1 protects against Ang II-induced vascular dysfunction. Results-Responses to CGRP in carotid and basilar arteries in vitro as well as cerebral arterioles in vivo were selectively enhanced in human RAMP1 transgenic mice compared to littermate controls (P<0.05), and this effect was prevented by a CGRP receptor antagonist (P<0.05). Thus, vascular responses to CGRP are normally RAMP1-limited. Responses of carotid arteries were examined in vitro after overnight incubation with vehicle or Ang II. In arteries from control mice, Ang II selectively impaired responses to the endothelium-dependent agonist acetylcholine by approximate to 50% (P<0.05) via a superoxide-mediated mechanism. In contrast, Ang II did not impair responses to acetylcholine in human RAMP1 transgenic mice. Conclusions-RAMP1 overexpression increases CGRP-induced vasodilation and protects against Ang II-induced endothelial dysfunction. These findings suggest that RAMP1 may be a new therapeutic target to regulate CGRP-mediated effects during disease including pathophysiological states in which Ang II plays a major role. (Stroke. 2010;41:2329-2334.)