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Overexpression of receptor activity modifying protein 1 enhances calcitonin gene‐related peptide‐induced vasodilation in the cerebral circulation
Author(s) -
Chrissobolis Sophocles,
Zhang Zhongming,
Lynch Cynthia M.,
Russo Andrew F.,
Faraci Frank M.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1384-c
Subject(s) - calcitonin gene related peptide , vasodilation , calcitonin , medicine , endocrinology , chemistry , receptor , genetically modified mouse , transgene , calcitonin receptor , pharmacology , neuropeptide , gene , biochemistry
Calcitonin gene‐related peptide (CGRP) is an extremely potent vasodilator that mediates vasodilation in response to activation of the trigeminal nerve. Neuronal release of CGRP limits vasoconstrictor responses and possibly vasospasm. The functional CGRP receptor consists of a calcitonin‐like receptor and receptor activity modifying protein‐1 (RAMP1). The aim of this study was to test the hypothesis that overexpression of RAMP1 enhances vasodilation to CGRP. We generated transgenic mice that overexpress human RAMP1 in most tissues, including the vasculature. The strategy was to use a conditional RAMP1 transgene that required removal of an upstream stop sequence by cre recombinase under control of the widely expressed adenoviral EIIa promoter. In cerebral arterioles of anesthetized mice, responses to CGRP (0.1 – 100 nM) were increased 2‐fold in transgenic mice vs littermate controls (n=7–8, P<0.05). Responses to acetylcholine and papaverine were unaltered. In the basilar artery in vitro, responses to CGRP in transgenic mice were also increased compared to controls. For example, the response to 10 nM CGRP was increased by ~50% (n=7, P<0.05). These studies indicate that overexpression of RAMP1 selectively enhances vasodilation to CGRP, suggesting that responses to CGRP are RAMP1‐limited. Thus, RAMP1 may represent a therapeutic target to increase vasodilator responses and CGRP‐mediated signaling.