Abstract
KEY POINTS: We provide evidence for two distinct functions of the NADPH oxidase Nox4 in angiogenesis using Nox4 knockout mice. First, Nox4 maintains vascular endothelial growth factor expression and prevents an increase in angiopoietin 1 expression, thereby contributing to angiogenesis in exercise. Second, deletion of Nox4, via an enhanced angiopoietin 1 expression, contributes to stabilization of new formed vessels and prevents an exacerbated neo-angiogenesis in oxygen-induced retinopathy. By contrast, Nox4 does not influence developmental angiogenesis. ABSTRACT: By producing H2 O2 , the NADPH oxidase Nox4 is involved in hypoxia-induced angiogenesis, as present in vascular remodelling of the hypertrophic heart or blood flow recovery after hind limb ischaemia. In the present study, we hypothesized that Nox4 contributes to proper capillary growth in the retina and in exercised muscles and investigated this in wild-type and Nox4(-/-) mice. Exercise, as induced by voluntary running in a running wheel or forced running on a treadmill, stimulated capillary growth in wild-type but not Nox4(-/-) mice. As an underlying mechanism, we identified both vascular endothelial growth factor (VEGF) expression to be reduced and angiopoietin 1 (Ang1) expression to be increased in response to Nox4 knockout. To differentiate the two factors, oxygen-induced retinopathy was investigated. In this model, deletion of Nox4 protected from neo-angiogenesis and stabilized the network of regrown vessels, which is a typical feature of Ang1. However the angiogenesis in the developing retina was similar between Nox4(-/-) and wild-type mice. Thus, Nox4 contributes to exercise- and hypoxia-induced angiogenesis through a dual mechanism of maintaining VEGF and preventing Ang-1 expression, whereas the developmental angiogenesis is Nox4 independent.