Endothelial nitric oxide synthase in the vascular wall: Mechanisms regulating its expression and enzymatic function
Demosthenous M., Antoniades C., Tousoulis D., Margaritis M., Marinou K., Stefanadis C.
Endothelial nitric oxide synthase (eNOS) is the main source of nitric oxide (NO) in the vascular wall, a molecule with anti-inflammatory, antithrombotic, vasorelaxant, antioxidant and finally antiatherogenic properties. eNOS is expressed in vascular endothelium, and it uses l-arginine as a substrate, while it also requires the presence of multiple co-factors such as tetrahydrobiopterin (BH4), nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) and others. In the presence of BH4 deficiency, this enzyme becomes uncoupled, and it is turned into a source of superoxide radicals instead of NO. Therefore, under these conditions which are present in patients with advanced atherosclerosis, eNOS in human vascular endothelium is largely a source of reactive oxygen species, inducing in this way atherogenesis. Therefore, the aim of future therapeutic strategies targeting atherosclerosis through regulation of eNOS physiology, should take into account that up-regulation of this enzyme in the vascular wall may not lead to a respective increase of NO bioavailability and improvement of vascular homeostasis, but it may actually induce intravascular oxidative stress, if intracellular bioavailability of eNOS co-factors is not simultaneously elevated. In conclusion, eNOS plays a critical role in the regulation of vascular homeostasis, and it is a therapeutic target against atherogenesis. © 2011 Association for Research into Arterial Structure and Physiology.