Figure 7. NOX signaling in vascular tone maintenance and diseases of the cardiovascular system.

Stimuli such as hypoxia, AngII or a high fat diet increase expression and enzymatic activity of NOX1, NOX2 and NOX4. O₂^·- production from NOX1 and NOX2 decreases nitric oxide (NO) availability causing an increase in vascular tone. Furthermore, increased oxidative stress leads to activation of HIF1 and its target genes such as VEGF, a master regulator of proliferation that underpins vascular remodeling seen in many vascular pathologies. NOX1 and NOX2 and NOX5 also acting via the activation of NFκB and decreased NO promote pro-inflammatory effects on vascular tissue leading to vascular remodeling, neointimal growth and atherosclerosis. Distinctly, NOX4 is generally deemed vasculoprotective in part the consequence of H₂O₂’s vasorelaxant properties and, in part, via activation of Nrf2. NOX5, activated through calcium-binding and acting via redox activation of kinases such as c-Src is involved in vascular hypercontractility and vascular dysfunction in hypertension and atherogenesis. A combination of more than one NOX is observed in cardiovascular diseases. MMP2/9: Matrix Metalloproteinase 2/9; NFκB: Nuclear Factor Kappa B; VEGF: Vascular Endothelial Growth Factor; HIF1: Hypoxia inducible factor 1. c-Src: Proto-oncogene, non-receptor tyrosine kinase Src.