Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors

Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors

Author Paredes-Gamero, Edgar Julian Autor UNIFESP Google Scholar
Medeiros, Valquiria Pereira de Autor UNIFESP Google Scholar
Farias, Eduardo Henrique Cunha de Autor UNIFESP Google Scholar
Justo, Giselle Zenker Autor UNIFESP Google Scholar
Trindade, Edvaldo da Silva Autor UNIFESP Google Scholar
Andrade-Lopes, Ana L. Google Scholar
Godinho, Rosely Oliveira Autor UNIFESP Google Scholar
Miranda, Antonio Autor UNIFESP Google Scholar
Ferreira, Alice Teixeira Autor UNIFESP Google Scholar
Tersariol, Ivarne Luis dos Santos Autor UNIFESP Google Scholar
Nader, Helena Bonciani Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Univ Fed Parana
Abstract Previous reports have shown that heparin may promote human hypotension and vascular relaxation by elevation of NO levels through unclear mechanisms. We hypothesized that endothelial muscarinic M-3 receptor activation mediates the heparin-induced vasodilation of rat aortic rings. the experiments were carried out using unfractionated heparin extracted from bovine intestinal mucosa, which elicited an endothelium and NO-dependent relaxation of aortic segments with maximal potency and efficacy (EC50: 100 +/- 10 mu mol/L; E-max: 41 +/- 3%). Atropine and 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide inhibitors reduced the heparin-dependent relaxation, indicating that M-3 muscarinic receptor is involved in this phenomenon. However, no direct binding of heparin to muscarinic receptors was observed. More importantly, studies performed using the arginine-glycine-aspartic acid peptide and 1-(1,1-dimethylethyl)-3-(1-naphthalenyl)-1H-pyrazolo[3,4-day]pyrimidin-4-amine, an Src family inhibitor, reduced by 51% and 73% the heparin-dependent relaxation, respectively, suggesting the coupling of heparin and M-3 receptor through extracellular matrix molecules and integrin. Furthermore, unfractionated heparin induced activation of focal adhesion protein kinase, Src, and paxillin. Finally, fluorescence resonance energy transfer approach confirmed the interaction of the M-3 receptor to integrin. Taken together, these data demonstrate the participation of M-3 receptor and integrin in heparin-dependent relaxation of vascular smooth muscle. These results provide new insights into the molecular mechanism and potential pharmacological action of heparin in vascular physiology. (Hypertension. 2010;56:713-721.)
Keywords heparin
muscarinic receptors
M-3 receptor
integrin
smooth muscle relaxation
aorta
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Financiadora de Estudos e Projetos
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Grant number FAPESP: 2006/61006-2
Date 2010-10-01
Published in Hypertension. Philadelphia: Lippincott Williams & Wilkins, v. 56, n. 4, p. 713-U282, 2010.
ISSN 0194-911X (Sherpa/Romeo, impact factor)
Publisher Lippincott Williams & Wilkins
Extent 713-U282
Origin http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.156877
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000281881400026
URI http://repositorio.unifesp.br/handle/11600/32927

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