BACKGROUND Hypoxia and indirect angiogenic factors may stimulate angiogenesis via induction of endothelial cell mitogen(s). To evaluate this hypothesis, we investigated whether low oxygen tension or cytokines known to promote neovascularization in vivo could modulate the expression of either vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in human vascular smooth muscle cells (SMCs). METHODS AND RESULTS SMCs were treated with platelet-derived growth factor BB (PDGF-BB) or transforming growth factor-beta 1 (TGF-beta 1) or exposed to low oxygen tension in serum-free medium. Northern analysis detected low basal levels of VEGF and bFGF mRNA in extracts of unstimulated SMCs. However, both VEGF and bFGF transcripts increased after administration of PDGF-BB (10 or 20 ng/mL) or TGF-beta 1 (0.1 to 10 ng/mL). Hypoxia was a potent stimulus for VEGF gene expression but had no apparent effect on bFGF steady-state mRNA levels. CONCLUSIONS These results indicate that certain indirect angiogenic cytokines, such as PDGF-BB or TGF-beta 1, may act via induction of bFGF and VEGF gene expression in cells resident near endothelial cells in vivo. Hypoxia constitutes a potent stimulus for VEGF gene expresion but does not regulate bFGF under the same experimental conditions.

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Background-Insulin resistance is associated with atherosclerosis, but its mechanism is unknown. It has been reported that insulin receptor substrate (IRS)-1 deficient ( IRS-1 Ϫ/Ϫ ) mice showed insulin resistance without type 2 diabetes, whereas the IRS-2 deficient (IRS-2 Ϫ/Ϫ ) mice showed insulin resistance with type 2 diabetes. Methods and Results-We investigated neointima formation in the IRS-1 Ϫ/Ϫ and IRS-2 Ϫ/Ϫ mice at 8 and 20 weeks. The IRS-2 Ϫ/Ϫ mice showed much greater neointima formation than the IRS-1 Ϫ/Ϫ and wild-type mice at 8 weeks. At 20 weeks, the IRS-2 Ϫ/Ϫ mice had greater neointima formation than the IRS-1 Ϫ/Ϫ mice, which showed more enhanced neointima formation than the wild-type mice. The IRS-1 Ϫ/Ϫ and IRS-2 Ϫ/Ϫ mice had dyslipidemia, hypertension, and insulin resistance. The IRS-2 Ϫ/Ϫ mice had more metabolic abnormalities than the IRS-1 Ϫ/Ϫ mice at 8 and 20 weeks. IRS-2 expression was detected, but IRS-1 expression was not detected in the vessels. Conclusions-The neointima formation in the IRS-1Ϫ/Ϫ and IRS-2 Ϫ/Ϫ mice appears to be related to abnormalities induced by the altered metabolic milieu in insulin-resistant states. Moreover, because neointima formation was much greater in the IRS-2 Ϫ/Ϫ mice than in the IRS-1 Ϫ/Ϫ mice at 8 and 20 weeks, it is suggested that a lack of IRS-2 renders the vasculature more susceptible to injury in the abnormal metabolic milieu, and IRS-2 may have a protective effect on neointima formation. We conclude that IRS-2 is protective and retards the development of neointima formation in insulin-resistant states.