Endothelium-derived nitric oxide (NO) activates the NO-epidermal growth factor receptor-mediated signaling pathway in bradykinin-stimulated angiogenesis

Endothelium-derived nitric oxide (NO) activates the NO-epidermal growth factor receptor-mediated signaling pathway in bradykinin-stimulated angiogenesis

Author Moraes, Miriam S. Google Scholar
Costa, Paulo E. Autor UNIFESP Google Scholar
Batista, Wagner L. Autor UNIFESP Google Scholar
Paschoalin, Taysa Autor UNIFESP Google Scholar
Curcio, Marli F. Autor UNIFESP Google Scholar
Borges, Roberta E. Autor UNIFESP Google Scholar
Taha, Murched O. Autor UNIFESP Google Scholar
Fonseca, Fabio V. Google Scholar
Stern, Arnold Google Scholar
Monteiro, Hugo P. Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
NYU
Univ Spiritu Santo Ecuador
Case Western Univ
Abstract Nitric oxide (NO) is involved in angiogenesis and stimulates the EGF-R signaling pathway. Stimulation of different endothelial cell lines with bradykinin (BK) activates the endothelial NO synthase (eNOS) and promotes EGF-R tyrosine phosphorylation. Increase in NO production correlated with enhanced phosphorylation of tyrosine residues and S-nitrosylation of the EGF-R. NO-mediated stimulatory effects on tyrosine phosphorylation of the EGF-R, where cGMP independent. Inhibition of soluble guanylyl cyclase followed by BK stimulation of human umbilical vein endothelial cells (HUVECs) did not change tyrosine phosphorylation levels of EGF-R. BK-stimulation of HUVEC promoted S-nitrosylation of the phosphatase SHP-1 and of p21Ras. Phosphorylation and activation of the ERK1/2 MAP kinases mediated by BK was dependent on the activation of the B2 receptor, of the EGF-R, and of p21 Ras. Inhibition of BK-stimulated S-nitrosylation prevented the activation of the ERK1/2 MAP kinases. Furthermore, activated ERK1/2 MAP kinases inhibited internalization of EGF-R by phosphorylating specific Thr residues of its cytoplasmic domain. BK-induced proliferation of endothelial cells was partially inhibited by the NOS inhibitor (L-NAME) and by the MEK inhibitor (PD98059). BK stimulated the expression of vascular endothelial growth factor (VEGF). VEGF expression was dependent on the activation of the EGF-R, the B2 receptor, p21Ras, and on NO generation. A Matrigel (R)-based in vitro assay for angiogenesis showed that BK induced the formation of capillary-like structures in HUVEC, but not in those cells expressing a mutant of the EGF-R lacking tyrosine kinase activity. Additionally, pre-treatment of BK-stimulated HUVEC with L-NAME, PD98059, and with SU5416, a specific inhibitor of VEGFR resulted in inhibition of in vitro angiogenesis. Our findings indicate that BK-mediated angiogenesis in endothelial cells involves the induction of the expression of VEGF associated with the activation of the NO/EGF-R/p21Ras/ERK1/2 MAP kinases signaling pathway. (C) 2014 Elsevier Inc. All rights reserved.
Keywords Angiogenesis
Bradykinin
Endothelial cells
Epidermal growth factor receptor
Nitric oxide
S-nitrosylation
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 2007/59617-6
FAPESP: 2010/19013-7
FAPESP: 2012/10470-1
Date 2014-09-15
Published in Archives of Biochemistry and Biophysics. New York: Elsevier B.V., v. 558, p. 14-27, 2014.
ISSN 0003-9861 (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 14-27
Origin http://dx.doi.org/10.1016/j.abb.2014.06.011
Access rights Closed access
Type Article
Web of Science ID WOS:000340701600003
URI http://repositorio.unifesp.br/handle/11600/38219

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