Receptor activity modifying protein‐1 (RAMP1) overexpression selectively enhances calcitonin gene‐related peptide‐induced vasodilation

Abstract

Calcitonin gene‐related peptide (CGRP), a potent vasodilator, is released during migraine and mediates vasodilation in response to trigeminal nerve activation. CGRP receptors consist of a calcitonin‐like receptor (CLR) and a receptor activity modifying protein‐1 (RAMP1). The aim of this study was to test whether RAMP1 overexpression enhances vasodilation to CGRP. Transgenic mice overexpressing human RAMP1 in most tissues, including blood vessels, were generated using a RAMP1 transgene under control of the widely expressed adenoviral EIIa promoter. In carotid artery in vitro, maximum relaxation to CGRP was increased ∼ 2‐fold in transgenic vs littermate controls, an effect that was inhibited by the CGRP receptor antagonist, CGRP (8–37) (P<0.05). Responses to adrenomedullin (which activates CLR coupled with RAMP2) were similar in both groups (P>0.05). In cerebral circulation, responses to CGRP were selectively increased ∼ 2‐fold in cerebral arterioles in vivo, and ∼ 70% in the basilar artery in vitro in transgenic vs control mice (P<0.05). These data indicate that RAMP1 overexpression selectively enhances vasodilation to CGRP, suggesting responses to CGRP are normally RAMP1‐limited. RAMP1 may represent a therapeutic target to inhibit increased responses to CGRP during migraine, or increase vasodilator responses and CGRP‐mediated signaling in conditions such as ischemia or vasospasm.