The L-Arginine-Nitric Oxide Pathway in the Vascular Smooth Muscle: Regulation and Pathophysiological Significance

Abstract

Nitric oxide is a multifunctional effector in the vascular system. In normal healthy blood vessels, nitric oxide is produced predominantly by endothelial cells which have a constitutively expressed nitric oxide synthase. Endothelial-derived nitric oxide plays a key role in the regulation of blood flow and the perfusion of vital organs. A second source of nitric oxide can be elicited in the blood vessel wall by inflammatory mediators. The exposure of cultures of smooth muscle cells from rat aorta to cytokines such as interleukin-1 β and tumor necrosis factor alpha causes after a delay of three to six hour the expression of an inducible type of nitric oxide synthase as indicated by the appearance of inducible nitric oxide synthase mRNA and protein. It is also supported by the fact that the cytokines evoke a time-dependent release of nitrite (a stable oxidation product of nitric oxide) and the intracellular accumulation of cyclic GMP in the smooth muscle cells. Both responses are inhibited by nitro L-arginine, an inhibitor of nitric oxide synthase. Similarly to endothelium-derived nitric oxide, nitric oxide derived from smooth muscle cells inhibits vascular tone and also prevents the activation of platelets. In addition, the endogenous cytokine-evoked production of nitric oxide in vascular smooth muscle cells brakes their proliferative response to mitogens. The expression of inducible nitric oxide synthase in vascular smooth muscle cells is controlled in a coordinated manner by factors-derived from both blood and vascular cells. Platelet-derived growth factor, transforming growth factor β, insulin-like growth factor and thrombin inhibit while epidermal growth factor, basic fibroblast growth factor and plasmin potentiate the expression of nitric oxide synthase in cytokine-activated vascular smooth muscle cells. These factors may prevent the production of large amounts of nitric oxide at sites of injury which are cytotoxic for most types of mammalian cells. As the in vivo endothelial denudation of the rat carotid artery by the repeated passage of a balloon catheter is associated with a time-dependent production of nitric oxide by the injured blood vessel wall; it is likely that smooth muscle-derived nitric oxide is an important mediator of the vascular response to injury causing local dilatation, limiting the activation of platelets and thus the formation of the thrombus and also curtailing the mitogenic response of factors released by platelets.