Caveolin-1 Regulation of Endothelial Nitric Oxide Synthase Function and Oxidative Stress in the Endothelium 57

Numerous cardiopulmonary, autoimmune, and inflammatory diseases, as well as cigarette smoke and dietary suppressants, induce significant oxidative stress resulting in endothelial cell dysfunction, hyperproliferation, and vasoocclusive vascular disease. Maintenance of normal endothelial cell function is thought to be mediated in part via tight control over endothelial nitric oxide synthase (eNOS) activity and “coupling” as regulated by the membrane-associated scaffolding protein caveolin-1 (Cav-1) and the phosphatase and tensin homolog (PTEN). This chapter summarizes the literature and highlights unanswered questions of how oxidative stress affects PTEN and Cav-1 negative regulatory functions and how unleashed eNOS enzymatic activity promotes endothelial dysfunction. Focus is given to how conversion of eNOS from a transient nitric oxide-producing enzyme to a peroxynitrite-generating system in states of oxidative stress due to environmental factors, inflammation, and mechanosensitive signaling gives rise to dysfunctional cardiovascular responses. Importantly, the noted vascular defects in absence of Cav-1 and PTEN that give rise to hyperproliferative endothelial cells and remodeled vasculature can be rescued by “recoupling,” inhibiting, or genetically deleting eNOS, supporting the notion that strict control of eNOS enzymatic activity and signaling is critical for maintaining vascular homeostasis.