Nitric oxide mediates cytotoxicity and basic fibroblast growth factor release in cultured vascular smooth muscle cells. A possible mechanism of neovascularization in atherosclerotic plaques.

Abstract

To define the pathophysiological role of nitric oxide (NO) released from vascular smooth muscle cells (VSMC), we examined whether NO released from VSMC induces cytotoxicity in VSMC themselves and adjacent endothelial cells (EC) using a coculture system. Prolonged incubation with interleukin-1 (IL-1) induced large amounts of NO release and cytotoxicity in VSMC. NG-Monomethyl-L-arginine, an inhibitor of NO synthesis, inhibited both NO release and cytotoxicity induced by IL-1. In contrast, DNA synthesis in cocultured EC was not inhibited but rather stimulated by prolonged incubation with IL-1 or sodium nitroprusside (SNP), a NO donor. However, IL-1 and SNP did not stimulate but inhibited DNA synthesis in EC alone. On the other hand, conditioned medium from VSMC incubated for a long period with IL-1 or SNP stimulated DNA synthesis in EC alone. Furthermore, the concentration of basic fibroblast growth factor in the conditioned medium was increased and correlated with the degree of cytotoxicity in VSMC. These results indicate that NO released from VSMC induces VSMC death, which results in release of basic fibroblast growth factor, which then stimulates adjacent EC proliferation. Thus, NO released from VSMC may participate in the mechanism of neovascularization in atherosclerotic plaques. (J. Clin. Invest. 1995. 95:669-676.)

Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide.

“…toxicity directly, NO may facilitate release of basic fibroblast growth factor from VSMC which, in turn, stimulates endothelial cell growth (39). Our data demonstrate a profound limitation of neointimal proliferation after a single, local administration of a durable, potent S-nitrosothiol.…”

Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia.

“…Recently, Jamieson and co-authors have demonstrated a correlation between apo(a) deposition within endothelial cells of vasa vasorum and the stage of atherosclerotic plaque in human cerebral vessels (37), suggesting a specific link between apo(a) receptor and the pathogenesis of atherosclerosis. Increased angiogenic factor expression in the adventitia has been demonstrated by several investigators (4,24,26,(38)(39)(40). In addition, certain angiogenic factors are also vascular smooth muscle cell and endothelial mitogens (17, 39,41,42).…”

Oxidized Low Density Lipoprotein and Lysophosphatidylcholine Stimulate Cell Cycle Entry in Vascular Smooth Muscle Cells

“…Others have suggested that FGF-2, which lacks a signal peptide for secretion, may be released in response to cell injury (45). Both oxidized LDL and lysoPC are known to injure cells, and vitamin E has been shown to inhibit the injury induced by oxidized LDL (9) and lysoPC.…”

“…FGF-2 lacks a signal peptide required for the cellular release of other secretory proteins (50). Results from a number of studies have suggested that cell injury can release FGF-2 (51), including a report that cell damage is required for FGF-2 secretion in cultured smooth muscle cells (45). However, it was reported that FGF-2 can be released from SMC without discernible injury by 25-hydroxycholesterol (52).…”