Testosterone Induces Vascular Smooth Muscle Cell Migration by NADPH Oxidase and c-Src-Dependent Pathways

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dc.contributor.authorChignalia, Andreia Z.
dc.contributor.authorSchuldt, Elke Z.
dc.contributor.authorCamargo, Livia L.
dc.contributor.authorMontezano, Augusto C.
dc.contributor.authorCallera, Glaucia E.
dc.contributor.authorLaurindo, Francisco R.
dc.contributor.authorLopes, Lucia R.
dc.contributor.authorAvellar, Maria Christina Werneck [UNIFESP]
dc.contributor.authorCarvalho, Maria Helena C.
dc.contributor.authorFortes, Zuleica B.
dc.contributor.authorTouyz, Rhian M.
dc.contributor.authorTostes, Rita C.
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniv Ottawa
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.date.accessioned2016-01-24T14:27:17Z
dc.date.available2016-01-24T14:27:17Z
dc.date.issued2012-06-01
dc.description.abstractTestosterone has been implicated in vascular remodeling associated with hypertension. Molecular mechanisms underlying this are elusive, but oxidative stress may be important. We hypothesized that testosterone stimulates generation of reactive oxygen species (ROS) and migration of vascular smooth muscle cells (VSMCs), with enhanced effects in cells from spontaneously hypertensive rats (SHRs). the mechanisms (genomic and nongenomic) whereby testosterone induces ROS generation and the role of c-Src, a regulator of redox-sensitive migration, were determined. VSMCs from male Wistar-Kyoto rats and SHRs were stimulated with testosterone (10(-7) mol/L, 0-120 minutes). Testosterone increased ROS generation, assessed by dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence (30 minutes [SHR] and 60 minutes [both strains]). Flutamide (androgen receptor antagonist) and actinomycin D (gene transcription inhibitor) diminished ROS production (60 minutes). Testosterone increased Nox1 and Nox4 mRNA levels and p47phox protein expression, determined by real-time PCR and immunoblotting, respectively. Flutamide, actinomycin D, and cycloheximide (protein synthesis inhibitor) diminished testosterone effects on p47phox. c-Src phosphorylation was observed at 30 minutes (SHR) and 120 minutes (Wistar-Kyoto rat). Testosterone-induced ROS generation was repressed by 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-day]pyrimidin-4-amine (c-Src inhibitor) in SHRs and reduced by apocynin (antioxidant/NADPH oxidase inhibitor) in both strains. Testosterone stimulated VSMCs migration, assessed by the wound healing technique, with greater effects in SHRs. Flutamide, apocynin, and 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-day] pyrimidin-4-amine blocked testosterone-induced VSMCs migration in both strains. Our study demonstrates that testosterone induces VSMCs migration via NADPH oxidase-derived ROS and c-Src-dependent pathways by genomic and nongenomic mechanisms, which are differentially regulated in VSMCs from Wistar-Kyoto rats and SHRs. (Hypertension. 2012; 59: 1263-1271.). Online Data Supplementen
dc.description.affiliationUniv São Paulo, Med Sch Ribeirao Preto, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP, Brazil
dc.description.affiliationUniv São Paulo, Inst Biomed Sci, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Sch Med, Inst Heart, São Paulo, Brazil
dc.description.affiliationUniv Ottawa, Ottawa Hosp Res Inst, Kidney Res Ctr, Ottawa, ON, Canada
dc.description.affiliationUniversidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, São Paulo, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipCanadian Institutes of Health Research
dc.format.extent1263-U478
dc.identifierhttp://dx.doi.org/10.1161/HYPERTENSIONAHA.111.180620
dc.identifier.citationHypertension. Philadelphia: Lippincott Williams & Wilkins, v. 59, n. 6, p. 1263-U478, 2012.
dc.identifier.doi10.1161/HYPERTENSIONAHA.111.180620
dc.identifier.issn0194-911X
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/34922
dc.identifier.wosWOS:000305176300036
dc.language.isoeng
dc.publisherLippincott Williams & Wilkins
dc.relation.ispartofHypertension
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjecttestosteroneen
dc.subjecthypertensionen
dc.subjectc-Srcen
dc.subjectNADPH oxidaseen
dc.subjectvascular smooth muscleen
dc.titleTestosterone Induces Vascular Smooth Muscle Cell Migration by NADPH Oxidase and c-Src-Dependent Pathwaysen
dc.typeinfo:eu-repo/semantics/article
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