Response to Letter by Tsuda

Abstract

Response to Letter by TsudaWe appreciate the interest and comments provided by Dr Tsuda regarding our recent publication. 1 In that study, we examined the hypothesis that increased expression of receptor activity-modifying protein-1 (RAMP1), a critical component of the calcitonin gene-related peptide (CGRP) receptor complex, enhances cerebrovascular effects of CGRP and protects against oxidative stress and angiotensin II-induced vascular dysfunction. One of our major findings was that RAMP1 overexpression increased CGRP-induced vasodilation in the carotid artery and in cerebral blood vessels.Chronic increases in activity of the sympathetic nervous system contribute to hypertension and other diseases. 2 As noted in Dr Tsuda's letter, previous studies suggest there may be interactions among CGRP, sympathetic nerves, and adrenergic receptor-mediated signaling. Based on this background, a question was raised as to whether changes in expression of RAMP1 affect the sympathetic nervous system. This in an interesting point and something we considered as our group pursued this area of study. Through central mechanisms, increases in circulating angiotensin II can increase sympathetic outflow. 2 Using a model of hypertension produced by systemic administration of angiotensin II, we found that increased expression of RAMP1 greatly reduced the pressor response to angiotensin II. 3 Mechanisms that appeared to contribute to this effect included alterations in baroreflex sensitivity, sympathetic outflow, and sympathetic-mediated vasoconstriction. 3 Although many specifics regarding the pathways involved remain to be defined, these findings support the concept that CGRP and RAMP1 interact with the autonomic nervous system in a manner that protects against hypertension.Angiotensin II promotes vascular dysfunction through several different mechanisms. 4,5 Dr Tsuda also asked whether CGRP suppressed effects of angiotensin II on sympathetic outflow in our recent study. 1 In addition to exerting effects centrally, angiotensin II has many direct effects on the vasculature. Angiotensin II can be produced locally and is known to contribute to vascular disease in the absence of hypertension. To determine if altered expression of RAMP1 protects against detrimental vascular effects of angiotensin II, we used a model that examined direct effects of angiotensin II on the vessel wall, thus avoiding potential systemic or neural effects of angiotensin II. 1 Our second major finding was that angiotensin II-induced endothelial dysfunction was prevented in RAMP1 transgenic mice. Although these findings do not exclude the possibility that RAMP1 protects the vasculature through effects on sympathetic outflow or other systemic effects when circulating levels of angiotensin II increase, our data provide direct evidence that protective effects of increased RAMP1 expression can occur locally at the level of the vessel wall. DisclosuresNone. Sophocles Chrissobolis, PhD