Journal article
Receptor Activity-Modifying Protein-1 Augments Cerebrovascular Responses to Calcitonin Gene-Related Peptide and Inhibits Angiotensin II-Induced Vascular Dysfunction
Stroke (1970), Vol.41(10), pp.2329-2334
2010
DOI: 10.1161/STROKEAHA.110.589648
PMID: 20814003
Abstract
Background and Purpose—Receptors for calcitonin gene-related peptide (CGRP) are composed of the calcitonin-like receptor in association with receptor activity-modifying protein-1 (RAMP1). CGRP is an extremely potent vasodilator and may protect against vascular disease through other mechanisms. Methods—We tested the hypothesis that overexpression of RAMP1 enhances vascular effects of CGRP using transgenic mice with ubiquitous expression of human RAMP1. Because angiotensin II (Ang II) is a key mediator of vascular disease, we also tested the hypothesis that RAMP1 protects against Ang II-induced vascular dysfunction. Results—Responses to CGRP in carotid and basilar arteries in vitro as well as cerebral arterioles in vivo were selectively enhanced in human RAMP1 transgenic mice compared to littermate controls (P<0.05), and this effect was prevented by a CGRP receptor antagonist (P<0.05). Thus, vascular responses to CGRP are normally RAMP1-limited. Responses of carotid arteries were examined in vitro after overnight incubation with vehicle or Ang II. In arteries from control mice, Ang II selectively impaired responses to the endothelium-dependent agonist acetylcholine by ≈50% (P<0.05) via a superoxide-mediated mechanism. In contrast, Ang II did not impair responses to acetylcholine in human RAMP1 transgenic mice. Conclusions—RAMP1 overexpression increases CGRP-induced vasodilation and protects against Ang II-induced endothelial dysfunction. These findings suggest that RAMP1 may be a new therapeutic target to regulate CGRP-mediated effects during disease including pathophysiological states in which Ang II plays a major role.
Details
- Title: Subtitle
- Receptor Activity-Modifying Protein-1 Augments Cerebrovascular Responses to Calcitonin Gene-Related Peptide and Inhibits Angiotensin II-Induced Vascular Dysfunction
- Creators
- Sophocles CHRISSOBOLIS - Department of Internal Medicine, Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City, Iowa, United StatesZhongming Zhang - Department of Molecular Physiology and Biophysics, Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City, Iowa, United StatesDale A KINZENBAW - Department of Internal Medicine, Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City, Iowa, United StatesCynthia M LYNCH - Department of Internal Medicine, Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City, Iowa, United StatesAndrew F RUSSO - Department of Molecular Physiology and Biophysics, Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City, Iowa, United StatesFrank M FARACI - Department of Pharmacology, Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
- Resource Type
- Journal article
- Publication Details
- Stroke (1970), Vol.41(10), pp.2329-2334
- DOI
- 10.1161/STROKEAHA.110.589648
- PMID
- 20814003
- NLM abbreviation
- Stroke
- ISSN
- 0039-2499
- eISSN
- 1524-4628
- Publisher
- Lippincott Williams & Wilkins; Hagerstown, MD
- Language
- English
- Date published
- 2010
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Cardiovascular Medicine; Craniofacial Anomalies Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984020790102771
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