Endothelialderived Inhibitors Of Smooth Muscle Cell Growth

Normally, smooth muscle cells are relatively refractory to growth stimuli and are maintained in a quiescent, differentiated state. It has been proposed, based on at least two lines of evidence, that the endothelium is important in maintaining this smooth muscle phenotype. First, removal of the endothelium experimentally allows initiation of the mitogenic response and, second, regrowth of normal endothelium inhibits further proliferation.106 One mechanism by which such a tonic inhibitory influence on smooth muscle cell growth could be effected is the secretion by endothelial cells of specific inhibitors of cell proliferation. Alternatively, the endothelium could be an effective barrier limiting access of bloodborne growth factors to vascular smooth muscle. Attention so far has focused on heparin and other glycosaminoglycans (including heparan sulfate) as possible candidates for endothelial-derived growth-inhibitory factors. Heparin inhibits VSMC mitogenesis and migration in vivo and in vitro, and reduces neointimal proliferation if administered during the first 3 days after vascular injury.107 However, the inhibition is not complete, and it seems likely that other endothelial cell factors may be involved. Another possibility is NO, which is usually associated with vascular relaxation. NO is released tonically from the endothelium of large arteries, which have a relatively minor role in the control of vascular tone, suggesting that it may have an additional function in these vessels. Studies on cultured VSMC have shown that pharmacologic agents such as sodium nitroprusside and 8-bromo-cyclic GMP, which mimic the effect of NO on vascular smooth muscle G kinase, can inhibit mitogenesis.108 This raises the possibility that NO may have an important role in maintaining the normal artery in a state refractory to mitogens. It is of interest that the myointimal proliferation in response to balloon injury can be inhibited by overexpression of NO synthase using gene transfer techniques.109'110 Finally, endothelial cells have been shown to make and secrete TGF-ft,— which is subsequently activated by smooth muscle cells. This growth factor inhibits smooth muscle growth directly111 and alters PDGF secretion,112 as well as extracellular matrix composition. The extracellular matrix may itself have a very important influence on smooth muscle proliferation.

The response of VSMCs to growth factors depends on the balance of the hormonal and environmental influences to which the cells are subjected. For example, intact arteries are relatively unresponsive to FGF, only showing a proliferative response when the endothelium has been damaged or removed.61 This raises the possibility that the cellular mechanism of action of factors secreted by the endothelial cells is to induce a protein or factor in smooth muscle cells that makes them refractory to mitogenic stimulation. One candidate for such a protein is a tyrosine phosphatase. As already noted, most growth factors activate a cascade of tyrosine kinases as an initial step in the mitogenic stimulus. The level of tyrosine in cellular proteins is also controlled by tyrosine phosphatases, enzymes that remove phosphates from tyrosine residues. Thus, in cells with very active tyrosine phosphatases, tyrosine kinases may be unable to induce a sustained phosphorylation of proteins on tyrosine, theoretically inhibiting the growth response. Evidence for such a mechanism of growth control is only now becoming available, with the discovery that somatostatins act as growth inhibitors in neoplastic cells through activation of a tyrosine phosphatase.52 Angiopeptin, a somatostatin analog, has been shown to inhibit neointimal proliferation after balloon injury,113 suggesting that activators of tyrosine phosphatases may be important in growth control in the vasculature. These observations raise the possibility that one of the mechanisms by which endothelial cells help to maintain smooth muscle quiescence is by the induction of tyrosine phosphatase activity in the smooth muscle cells.

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