Evidence for a Protective Role for Receptor Activity Modifying Protein‐1 (RAMP1) in Angiotensin II‐Induced Endothelial Dysfunction

Abstract

Angiotensin II (Ang II) plays a major role in hypertension and causes vascular oxidative stress and endothelial dysfunction. Calcitonin gene‐related peptide (CGRP), a potent vasodilator, reportedly has antioxidant properties in vascular cells in culture. CGRP receptors consist of a calcitonin‐like receptor and a receptor activity modifying protein‐1 (RAMP1). The aim of this study was to test if RAMP1 overexpression protects against Ang II‐induced endothelial dysfunction. Transgenic mice overexpressing human RAMP1 (hRAMP1) in most tissues (including blood vessels) were generated using a RAMP1 transgene under control of the CX1 promoter. Responses of carotid artery were examined in vitro following 22 hour incubation with vehicle or Ang II (10 nmol/L). Maximum relaxation to the endothelium‐dependent vasodilator acetylcholine (ACh) was impaired by ~40% in Ang II‐treated vs vehicle‐treated vessels from control mice (P<0.05). In contrast, in hRAMP1 mice, maximum relaxation to ACh was similar in vehicle and Ang II‐treated vessels (P>0.05), suggesting RAMP1 overexpression protects against Ang II‐induced endothelial dysfunction. Responses to nitroprusside were similar in both groups of mice and unaffected by Ang II treatment (P>0.05). RAMP1 may represent a therapeutic target to protect endothelial function in conditions where Ang II plays a major role, including hypertension.