NADPH oxidase 1/4 inhibition attenuates the portal hypertensive syndrome via modulation of mesenteric angiogenesis and arterial hyporeactivity in rats

Aim: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) plays key roles in the development of portal hypertension (PHT) and represents a potential therapeutic method. The objective of this study was to investigate whether pharmacological inhibition of NADPH oxidase activity could ameliorate PHT in rats. Method: PHT model was established by partial portal vein ligation (PPVL). Rats were treated with 30 mg/kg GKT137831 (the most specific Nox1/4 inhibitor) or vehicle daily by gavage for 14 days beginning at the day of PPVL or sham operation (SO). Hemodynamics, severity of portal-systemic shunting, vascular contractility, vascular endothelial growth factor (VEGF), VEGFR-2, CD31, AKT, phospho-AKT (p-AKT, at Ser473), endothelial nitric oxide synthase (eNOS), and phospho-eNOS (p-eNOS, at Ser1177) expressions were evaluated. Nitric oxide (NO) production and oxidative stress in mesenteric arteries, and hydrogen peroxide (H2O2) in both mesenteric tissues and arteries were measured. Result: Inhibition of NOX1/4 with GKT137831 significantly decreased cardiac index, increased portal flow resistance, reduced portal pressure (PP), portal blood flow, mesenteric angiogenesis and portal-systemic shunting (PSS) in PPVL rats. GKT137831 reduced the production of H2O2, down regulated mesenteric angiogenesis markers (CD31, vascular endothelial growth factor (VEGF) and VEGFR-2 expression. Compared with controls), the mesenteric artery contraction to norepinephrine (NE) was impaired in PPVL rats, which was reversed by exposure to GKT137831. In addition, GKT137831 markedly decrease NADPH oxidase activity and ROS production in mesenteric arteries, and reduced NO production by decreasing the level of phosphor-AKT and eNOS. Conclusion: Inhibition of NOX1/4 decreased PP, ameliorated hyperdynamic circulation, mesenteric angiogenesis and arterial hyporesonse in portal hypertensive rats. Pharmacological inhibition of NOX1/4 activity may be a potential treatment for PHT-related complications. (C) 2018 Elsevier Masson SAS. All rights reserved.