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Reactivity of renal and mesenteric resistance vessels to angiotensin II is mediated by NOXA1/NOX1 and superoxide signaling
Stevenson, M. D., Vendrov, A. E., Yang, X., Chen, Y., Navarro, H. A., Moss, N., Runge, M. S., Arendshorst, W. J., & Madamanchi, N. R. (2023). Reactivity of renal and mesenteric resistance vessels to angiotensin II is mediated by NOXA1/NOX1 and superoxide signaling. American Journal of Physiology - Renal Physiology, 324(4), F335-F352. https://doi.org/10.1152/ajprenal.00236.2022
Activation of NADPH oxidase (NOX) enzymes and the generation of reactive oxygen species (ROS) and oxidative stress regulate vascular and renal function and contribute to the pathogenesis of hypertension. This study examined the role of NOXA1/NOX1 function in vascular reactivity of renal and mesenteric resistance arteries/arterioles of wild-type and Noxa1-/- mice. A major finding is that the renal blood flow (RBF) is less sensitive to acute stimulation by Ang II (Angiotensin II) in Noxa1-/- mice compared with wild-type mice, with a direct action on resistance arterioles independent of nitric oxide (NO) bioavailability. These functional studies are reinforced by immunofluorescence evidence of NOXA1/NOX1 protein presence in the renal arteries, afferent arterioles, and glomeruli, as well as their upregulation by Ang II. In contrast, the renal vascular response to the thromboxane mimetic U46619 is effectively blunted by NO and is similar in both mouse genotypes and thus independent of NOXA1/NOX1 signaling. However, phenylephrine and Ang II-induced contraction of isolated mesenteric arteries is less pronounced and buffering of vasoconstriction after acetylcholine and nitroprusside stimulation is reduced in Noxa1-/- mice, suggesting endothelial NO-dependent mechanisms. An involvement of NOXA1/NOX1/O2•- signaling in response to Ang II was demonstrated with the specific NOXA1/NOX1 assembly inhibitor C25 and the nonspecific NOX inhibitor diphenyleneiodonium chloride (DPI) in cultured vascular smooth muscle cells and isolated mesenteric resistance arteries. Collectively, our data indicate that the NOX1/NOXA1/O2•- pathway contributes to acute vasoconstriction induced by Ang II in the renal and mesenteric vascular beds and may contribute to Ang II-induced hypertension.