151 Nox5 induces vascular dysfunction and arterial remodelling independently of blood pressure elevation in ang ii-infused nox5-expressing mice

Abstract

Nox5 is a unique Ca2+-sensitive Nox isoform that is expressed in human vascular smooth muscle cells (VSMC). Although Nox5 has been implicated in diabetic nephropathy, its role in vascular function and development of hypertension remain unclear. Nox5 is not expressed in rodents, and accordingly we generated humanised Nox5 mice with Nox5 expressed in a VSMC-specific manner (Nox5SM22). Control (wild-type) and Nox5SM22 mice were infused with Ang II (600 ng/Kg/day). Blood pressure (BP) was assessed by tail-cuff. Vascular function and structure of resistance arteries were measured by myography. Ang II increased BP in WT and Nox5SM22 mice with no significant differences. Arteries from Nox5SM22 mice exhibited reduced endothelium-dependent relaxation versus WT controls (%ACh relaxation: 55.1+/-4 vs ctl: 81.6+/-7%). Fasudil (Rho kinase inhibitor)-induced relaxation was reduced in Nox5SM22 mice versus controls (%Fas relaxation: 111.3+/-11 vs ctl: 166.6+/-8%) (p<0.05). Ang II increased the maximal contraction to U46619 (thromboxane A2 mimetic) in WT (115.8+/-2 vs untreated: 101.4+/-2%) and Nox5SM22 (121.3+/-3 vs untreated: 99.1+/-2) (p<0.05) and induced endothelial dysfunction in all groups. Fasudil-induced relaxation was impaired by Ang II in WT (102.7+/-6 vs untreated: 166.6+/-8%, p<0.05) but not further impaired in Nox5SM22 mice (114.9+/-6 vs untreated: 111.3+/-11%). Ang II increased cross-sectional area (CSA) and lumen diameter) while in Nox5SM22 mice, Ang II increased wall thickness, wall-tolumen ratio, CSA and decreased lumen diameter, with associated increased vascular stiffness. Our findings indicate that in mice expressing human Nox5 in VSMCs, endothelium-dependent relaxation is impaired, fasudil-mediated vasodilation is attenuated and vessels undergo exaggerated hypertrophic inward remodelling with increased stiffness; processes that occur independently of BP elevation. These data suggest an important role for Nox5 in Ang II-induced vascular dysfunction and remodelling, but not in the development of hypertension. Moreover, we identify Rho kinase as a putative target for Nox5-induced vascular injury. We provide novel insights into Nox5 vascular biology and demonstrate that vascular Nox5 actions are dissociated from BP effects.