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Rapamycin inhibits transforming growth factor β-induced peritoneal angiogenesis by blocking the secondary hypoxic response.

Sekiguchi Y, Zhang J, Patterson S, Liu L, Hamada C, Tomino Y, Margetts PJ - J. Cell. Mol. Med. (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

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Hypothesized interaction between direct effects of TGFβ and secondary effects of hypoxia. TGFβ has direct effects on peritoneal tissues including EMT, cellular proliferation, fibrosis and angiogenesis. The TGFβ-induced expanding extracellular matrix is hypoxic, and this drives a similar but delayed response. The hypoxia-induced effects are blocked by rapamycin, whereas rapamycin has no effect of the TGFβ-induced effects (denoted by x). The profibrotic effects of hypoxia are Smad3 dependent. In vitro, rapamycin up-regulates type 1 collagen in TGFβ-treated mesothelial cells (dashed arrow).
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fig10: Hypothesized interaction between direct effects of TGFβ and secondary effects of hypoxia. TGFβ has direct effects on peritoneal tissues including EMT, cellular proliferation, fibrosis and angiogenesis. The TGFβ-induced expanding extracellular matrix is hypoxic, and this drives a similar but delayed response. The hypoxia-induced effects are blocked by rapamycin, whereas rapamycin has no effect of the TGFβ-induced effects (denoted by x). The profibrotic effects of hypoxia are Smad3 dependent. In vitro, rapamycin up-regulates type 1 collagen in TGFβ-treated mesothelial cells (dashed arrow).

Mentions: Our results indicate that the expanding extracellular matrix induced by TGFβ in the peritoneum is hypoxic, and this hypoxia potentiates and prolongs fibrogenesis and angiogenesis. We interpret our results to suggest that after overexpression of TGFβ1, there is a period of TGFβ1-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 TGFβ1-mediated events (Fig. 10). This is supported by cell culture experiments where rapamycin blocks hypoxia-induced VEGF, but has no effect on TGFβ1-induced VEGF.


Rapamycin inhibits transforming growth factor β-induced peritoneal angiogenesis by blocking the secondary hypoxic response.

Sekiguchi Y, Zhang J, Patterson S, Liu L, Hamada C, Tomino Y, Margetts PJ - J. Cell. Mol. Med. (2012)

Hypothesized interaction between direct effects of TGFβ and secondary effects of hypoxia. TGFβ has direct effects on peritoneal tissues including EMT, cellular proliferation, fibrosis and angiogenesis. The TGFβ-induced expanding extracellular matrix is hypoxic, and this drives a similar but delayed response. The hypoxia-induced effects are blocked by rapamycin, whereas rapamycin has no effect of the TGFβ-induced effects (denoted by x). The profibrotic effects of hypoxia are Smad3 dependent. In vitro, rapamycin up-regulates type 1 collagen in TGFβ-treated mesothelial cells (dashed arrow).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822704&req=5

fig10: Hypothesized interaction between direct effects of TGFβ and secondary effects of hypoxia. TGFβ has direct effects on peritoneal tissues including EMT, cellular proliferation, fibrosis and angiogenesis. The TGFβ-induced expanding extracellular matrix is hypoxic, and this drives a similar but delayed response. The hypoxia-induced effects are blocked by rapamycin, whereas rapamycin has no effect of the TGFβ-induced effects (denoted by x). The profibrotic effects of hypoxia are Smad3 dependent. In vitro, rapamycin up-regulates type 1 collagen in TGFβ-treated mesothelial cells (dashed arrow).
Mentions: Our results indicate that the expanding extracellular matrix induced by TGFβ in the peritoneum is hypoxic, and this hypoxia potentiates and prolongs fibrogenesis and angiogenesis. We interpret our results to suggest that after overexpression of TGFβ1, there is a period of TGFβ1-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 TGFβ1-mediated events (Fig. 10). This is supported by cell culture experiments where rapamycin blocks hypoxia-induced VEGF, but has no effect on TGFβ1-induced VEGF.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Show MeSH
Related in: MedlinePlus