REGULATION OF SMOOTH-MUSCLE CELL-GROWTH - BY ENDOTHELIUM-DERIVED FACTORS

The endothelium is a source of molecules that either stimulate or inhi bit the proliferation of the underlying smooth muscle cells. In the no rmal, healthy vessel wall the smooth muscle cells are quiescent, but t hey proliferate when damage to the endothelium occurs. The implication of such observations is that although the endothelium provides a sour ce of growth factors, their stimulatory activity on smooth muscle cell s is countered by endothelium-derived growth inhibitors. The inhibitor s appear to comprise at least 3 distinct types of molecules: heparin/h eparan sulfate; transforming growth factor beta; and nitric oxide. Eac h molecule inhibits growth of cultured smooth muscle cells by mechanis ms that remain to be elucidated and are discussed in this communicatio n. Heparin/heparan sulfate is the most thoroughly characterized of the 3, and has been used for clinical intervention to prevent restenosis. Transforming growth factor beta exhibits bimodal activity on growth, acting as a stimulant at low levels and as an inhibitor at elevated co ncentrations. Nitric oxide mediated vasorelaxation is dependent upon a ctivation of soluble guanylate cyclase. Because elevation of cyclic gu anosine monophosphate in smooth muscle cells depresses their prolifera tion, nitric oxide would appear to possess the properties necessary to inhibit vascular smooth muscle cell proliferation.