NOS3 and endothelial dysfunction: ,41,42 Central to the pathogenesis of ARED are the decline in aging-related endothelial nitric oxide synthase activity—attributable to oxidative stress-induced dephosphorylation—exhaustion of endothelial progenitor cells, and abnormal vascular remodeling resulting from imbalances between matrix MMPs and tissue inhibitors of metalloproteinases, all of which contribute to endothelial dysfunction.43-47