ABNORMAL ENDOTHELIAL-MEDIATED REGULATION OF VASCULAR TONE IN ARTERIOSCLEROSIS

Knowledge regarding the endothelial-derived relaxing factor (EDRF) has substantially increased over recent years. The chemical identification of EDRF as nitric oxide (NO) and the discovery of the NO-pathway started an exciting research field with new insights into the regulation of many biologic processes. Concerning regulation of the vascular tone, EDRF(NO) is one of the most potent relaxant substances known; in addition, EDRF(NO) is a potent inhibitor of platelet adhesion and aggregation and leukocyte adhesion to the vascular wall; furthermore, EDRF(NO) is probably an inhibitor of smooth muscle cell proliferation. This profile of EDRF(NO) may be an important part of the anti-arteriosclerotic function of intact endothelial cells. In animal models of hypercholesterolemia and in patients with hypercholesterolemia and/or arteriosclerosis, the EDRF(NO) mechanism is impaired or almost abolished (= endothelial dysfunction). The reason for this abnormal endothelial function is not fully understood and may be multifactorial; it has been suggested that this endothelial dysfunction is due to an accelerated breakdown of EDRF(NO) by oxidixed low density lipoprotein and/or oxygen derived free radicals. In addition, there may be an increased release of vasoconstrictive substances, e.g., endothelin-1, from endothelial cells which may override the relaxant effects of EDRF (NO). This abnormal function of the endothelium (in terms of the EDRF(NO) mechanism) appears to be reversible in animal models and in patients with hypercholesterolemia, and is accomplished by normalizing plasma cholesterol levels.