Rapamycin inhibits transforming growth factor Î²-induced peritoneal angiogenesis by blocking the secondary hypoxic response.
Bottom Line: In primary mesothelial cell culture, rapamycin had no effect on TGFβ-induced vascular endothelial growth factor (VEGF) but did suppress hypoxia-induced VEGF.The fibrogenic effects of HIF1α were Smad3 dependent.The hypoxic response is mediated partly through HIF1α and the mTOR inhibitor rapamycin blocks the hypoxic-induced angiogenic effects but does not affect the direct TGFβ-mediated fibrosis and angiogenesis.
Affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.Show MeSH
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Mentions: Our results indicate that the expanding extracellular matrix induced by TGFÎ² in the peritoneum is hypoxic, and this hypoxia potentiates and prolongs fibrogenesis and angiogenesis. We interpret our results to suggest that after overexpression of TGFÎ²1, there is a period of TGFÎ²1-driven fibrosis and angiogenesis. This is followed by a hypoxia-mediated prolongation of this initial wound healing response. The later hypoxia-driven response is inhibited by rapamycin, but rapamycin has no effect on the earlier TGFÎ²1-mediated events (Fig. 10). This is supported by cell culture experiments where rapamycin blocks hypoxia-induced VEGF, but has no effect on TGFÎ²1-induced VEGF.
Affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.