Endothelial Control of Vasomotor Function
he endothelial cells have an obligatory role in the relaxation of isolated arteries in response to acetylcholine. 1 This simple but seminal observation has brought recognition of the pivotal role of the endothelium in contributing to the physiological regulation of vasomotor control. This endothelium-dependent control is exerted by the release of several diffusible substances [(endotheliumderived relaxing (EDRF) and contracting (EDCF) factors] from the endothelial cells. This essay summarizes
... essay summarizes briefly the observations obtained mainly in the author's laboratory that have determined how the secretion by endothelial cells of the relaxing factors underlies moment-to-moment changes in the tone of the surrounding vascular smooth muscle cells, and how the inability of the endothelial cells to do so eventually initiates atherosclerosis and thus vascular disease. For detailed references, the reader is referred to several more exhaustive overviews.             Endothelium-Derived Relaxing Factors (Fig 1) Endothelium-Derived Nitric Oxide The short-lived diffusible, nonprostanoid substance that mediates the endothelium-dependent relaxation to acetylcholine originally described by Furchgott and Zawadzki 1 has been identified as nitric oxide (NO). NO is formed in endothelial cells from the guanidine-nitrogen terminal of L-arginine, by the constitutive NO-synthase III (endothelial NO-synthase, eNOS). The activation of NO synthase III depends on the intracellular concentration of calcium ions in the endothelial cells, as it is Ca 2+ -calmodulin-dependent. The activity of the enzyme requires cofactors such as reduced nicotinamide-adenine-dinucleotide phosphate, and 5,6,7,8 tetra-hydrobiopterin. Endothelial NO-synthase can be inhibited competitively by L-arginine analogs such as N G -monomethyl-L-arginine or N G -nitro-L-arginine. NO diffuses to the vascular smooth muscle cells and relaxes them mainly by stimulating the cytosolic enzyme, soluble guanylate cyclase, which catalyzes the production of cyclic 3'5'-guanosine monophosphate (cGMP), leading to inhibition of the contractile process. NO is a major contributor to endothelium-dependent relaxation in large arteries, including the coronary, systemic, mesenteric, pulmonary and cerebral arteries. In vivo, inhibitors of NO synthase cause vasoconstriction in most vascular beds and an increase in systemic arterial pressure in both animals and humans.              NO is released not only towards the underlying vascular smooth muscle, but also into the lumen of the blood vessel. Thus, at the interface between the blood and the vascular wall, NO inhibits the adhesion of platelets and white cells to the endothelium. It acts (in strong synergy with prostacyclin) to inhibit platelet aggregation. 3, 4, 9, 14 It also inhibits the growth of the vascular smooth muscle cells and prevents the production of adhesion molecules and endothelin (Fig 2) . 15 The production of NO is regulated by physical and humoral stimuli. Thus, the shear stress exerted by the flowing blood on the endothelial cells is one of the main factors determining the local release of NO. This underlies flowdependent vasodilatation. Several hormones and autacoids Circ J 2003; 67: 572 -575 T Fig 1. Role of the increase in cytosolic calcium concentration in the release of endothelium-derived relaxing factors (EDRF). Endothelial receptor activation induces an influx of calcium into the cytoplasm of the endothelial cell; following interaction with calmodulin, this activates NO-synthase and cyclooxygenase, and leads to the release of endothelium-derived hyperpolarizing factor (EDHF). NO causes relaxation by activating the formation of cyclic GMP (cGMP) from GTP. EDHF causes hyperpolarization and relaxation by opening K + channels. Prostacyclin (PGI2) causes relaxation by activating adenylate cyclase (AC) which leads to the formation of cyclic AMP (cAMP). Any increase in cytosolic calcium (including that induced by the calcium ionophore A23187) causes the release of relaxing factors. When agonists activate the endothelial cells, an increase in inositol phosphate (IP3) may contribute to the increase in cytoplasmic Ca 2+ by releasing it from the sarcoplasmic reticulum (SR) (From Vanhoutte PM, Boulanger CM, Vidal M, Mombouli JV. Endothelium-derived mediators and the renin-angiotensin system. In: Robertson JIS, Nicholls MG, editors. The renin -angiotensin system. Gower Medical Publishing; 1993: by permission).