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Calcitonin Gene-Related Peptide Receptor Activation by Receptor Activity-Modifying Protein-1 Gene Transfer to Vascular Smooth Muscle Cells

Department of Physiology and Biophysics, University of Iowa (Z.Z., A.F.R.), Iowa City, Iowa 52242; and Department of Neurobiology and Anatomy, University of Rochester (I.M.D.), Rochester, New York 14642

Address all correspondence and requests for reprints to: Dr. Andrew F. Russo, Department of Physiology and Biophysics, 51 Newton Road, University of Iowa, Iowa City, Iowa 52242. E-mail: andrew-russo{at}uiowa.edu.

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator that plays a protective role in the cardiovascular system. The receptor for CGRP is an unusual complex of the G protein-coupled calcitonin-like receptor and an obligate receptor activity modifying protein-1 (RAMP1). In this report we provide the first evidence that RAMP1 is rate limiting in vascular smooth muscle cells. Although cultured rat aorta smooth muscle cells express calcitonin like-receptor and RAMP1, we found that CGRP is not a potent activator of the receptor. After overexpression of RAMP1 by adenoviral gene transfer, there was a striking increase in CGRP-induced production of cAMP, with a 75-fold decrease in the EC₅₀ and a 1.5-fold increase in the maximal response. The biological consequence of this increased receptor activity was observed in three different paradigms. First, RAMP1 gene transfer caused a CGRP-dependent decrease in cell proliferation. Second, RAMP1 and CGRP treatment led to a 3-fold greater free radical-induced reduction in cell number. Finally, RAMP1 gene transfer resulted in a 5-fold CGRP-dependent increase in terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling-positive apoptotic cells upon serum withdrawal. The mechanisms underlying these effects involved cAMP-dependent pathways. We propose that RAMP1 gene transfer may be an effective strategy for increasing the effectiveness of CGRP-induced decrease in restenosis after aortic angioplasty.

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