rapamycin inhibits proliferation of hemangioma endothelial cells by reducing hif-1-dependent expression of vegf雷帕霉素抑制扩散血管瘤内皮细胞减少hif-1-dependent vegf的表达.pdfVIP

Rapamycin Inhibits Proliferation of Hemangioma Endothelial Cells by Reducing HIF-1-Dependent Expression of VEGF Damian Medici1,2*, Bjorn R. Olsen2,3 1 Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Medical School, Boston, Massachusetts, United States of America, 3 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America Abstract Hemangiomas are tumors formed by hyper-proliferation of vascular endothelial cells. This is caused by elevated vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2 (VEGFR2). Here we show that elevated VEGF levels produced by hemangioma endothelial cells are reduced by the mTOR inhibitor rapamycin. mTOR activates p70S6K, which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 (HIF-1). VEGF is a known HIF-1 target gene, and our data show that VEGF levels in hemangioma endothelial cells are reduced by HIF-1a siRNA. Over-expression of HIF-1a increases VEGF levels and endothelial cell proliferation. Furthermore, both rapamycin and HIF-1a siRNA reduce proliferation of hemangioma endothelial cells. These data suggest that mTOR and HIF-1 contribute to hemangioma endothelial cell proliferation by stimulating an autocrine loop of VEGF signaling. Furthermore, mTOR and HIF-1 may be therapeutic targets for the treatment of hemangiomas. Citation: Medici D, Olsen BR (2012) Rapamycin Inhibits Proliferation of Hemangioma Endothelial Cells by Reducing HIF-1-Dependent Expression of VEGF. PLoS ONE 7(8): e42913. doi:10.1371/journal.pone.0042913 Editor: Irina V. Lebedeva, Enzo Life Sciences, Inc., United States of