Aim: : The aim of this study was to analyse the signalling pathways involved in H2O2 vascular responses in hypertension.
Methods: Vascular function, thromboxane A2 (TXA2) production, oxidative stress and protein expression were determined in mesenteric resistance arteries (MRAs) from hypertensive (spontaneously hypertensive rats, SHR) and normotensive Wistar Kyoto (WKY) rats.
Results: H2O2 and the TP agonist U46619 induced greater contractile responses in MRA from SHR than WKY. Moreover, H2O2 increased TXA2 production more in SHR than in WKY. The c-Src inhibitor PP1 reduced H2O2 and U46619-induced contraction and TXA2 release in both strains. The ERK1/2 inhibitor PD98059 reduced H2O2 but not U46619-induced contraction only in SHR arteries. The Rho kinase inhibitor Y26372 reduced H2O2 and U46619-induced contractions only in SHR arteries. Basal c-Src, ERK1/2 and Rho kinase expression were greater in MRA from SHR than WKY. In SHR, the combination of PD98059 with the TP antagonist SQ29548 but not with Y27632 inhibited the H2O2 contraction more than each inhibitor alone. H2O2 and U46619 increased NAD(P)H oxidase activity and O2 production and decreased mitochondrial membrane potential in vessels from SHR. The effects induced by H2O2 were abolished by inhibitors of TXA2 synthase, ERK1/2 and c-Src. The mitochondrial antioxidant mitoTEMPO reduced H2O2-induced contraction and NAD(P)H oxidase activation.
Conclusion: In arteries from WKY, c-Src mediates H2O2 contractile responses by modulating TXA2 release and TXA2 effect. In SHR, H2O2 induces c-Src dependent TXA2 release that provokes vascular contractile responses through Rho kinase, c-Src and O2 from NAD(P)H Oxidase and mitochondria. Moreover, ERK1/2 activation contributes to H2O2 contraction in SHR through effects on mitochondria/NAD(P)H Oxidase.