Endothelial dysfunction: From physiology to therapy

The endothelium controls the tone of the underlying vascular smooth muscle mainly through the production of vasodilator mediators. In some cases. this function is hampered by the release of constrictor substances. The endothe lial mediators are also involved in the regulation by the endothelium of va scular architecture and the blood cell-vascular wall interactions. The endo thelium-derived factors comprise nitric oxide (NO), prostacyclin, and a sti ll unknown endothelium-derived hyperpolarizing factor(s) (EDHF). In most va scular diseases, the vasodilator function of the endothelium is attenuated. In advanced atherosclerotic lesions, endothelium-dependent vasodilatation may even be abolished. Various degrees and forms of endothelial dysfunction exist, including (1) the impairment of G(alpha i) proteins, (2) less relea se of NO, prostacyclin and/or EDHF, ( 3) increased release of endoperoxides . (4) increased production of reactive oxygen species, (5) increased genera tion of endothelin-l, and (6) decreased sensitivity of the vascular smooth muscle to NO, prostacyclin and/or EDHF. The levels of bradykinin and angiot ensin II within the vascular wall are controlled by angiotensin-converting enzyme (ACE). ACE degrades bradykinin and generates angiotensin II. Bradyki nin stimulates endothelial cells to release vasodilators. The actions of th e kinin are maintained despite endothelial dysfunction, except in very seve re arterial lesions. Angiotensin II may be in part responsible for endothel ial dysfunction because it induces resistance to the vasodilator action of NO. Thus, impairment of the generation of angiotensin II blocks the direct and indirect vasoconstrictor effect of the peptide. By potentiating bradyki nin. ACE inhibitors promote the release of relaxing vasodilator mediators t o restore vasodilator Function, and to prevent platelet aggregation as well as the recruitment of leukocytes to the vascular wall. (C) 1999 Academic P ress.