Rapamycin inhibits transforming growth factor β-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: As previously demonstrated , rapamycin significantly reduced HIF1α and VEGF expression in mesothelial cells exposed to 1% oxygen for 12 or 24 hrs (Fig. 5). Hypoxia significantly up-regulated HIF1α protein expression. Rapamycin significantly decreased HIF1α protein expression at both 12 and 24 hrs (Fig. 5A and B). By two-way ANOVA, hypoxia significantly increased VEGF expression after 24 hrs of hypoxia. Rapamycin significantly decreased hypoxia-induced VEGF expression in a dose-dependent manner (Fig. 5C).
Affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.