CD105 prevents apoptosis in hypoxic endothelial cells

被引:129
作者
Li, CG
Issa, R
Kumar, P
Hampson, IN
Lopez-Novoa, JM
Bernabeu, C
Kumar, S [1 ]
机构
[1] Univ Manchester, Sch Med, Dept Pathol, Manchester M13 9PT, Lancs, England
[2] Christie Hosp, Manchester M13 9PT, Lancs, England
[3] Manchester Metropolitan Univ, Dept Sci Biol, Manchester M15 6BH, Lancs, England
[4] Univ Manchester, St Marys Hosp, Acad Unit Obstet & Gynaecol, Manchester M13 0JH, Lancs, England
[5] Univ Salamanca, Inst Reina Sofis Invest Nefrol, Dept Physiol & Pharmacol, E-37008 Salamanca, Spain
[6] CSIC, Ctr Invest Biol, Dept Immunol, E-28006 Madrid, Spain
关键词
hypoxia; CD105; endothelial cells; TGF beta; apoptosis;
D O I
10.1242/jcs.00470
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
CD105, a marker of endothelial cells, is abundantly expressed in tissues undergoing angiogenesis and is a receptor for transforming growth factor beta. The pivotal role of CD105 in the vascular system was demonstrated by the severe vascular defects that occur in CD105-knockout mice, but the exact mechanisms for CD105 regulation of vascular development have not been fully elucidated. In light of the function of CD105 and the importance of hypoxia in neovascularisation, we speculated that CD105 is involved in hypoxia-initiated angiogenesis. Using tissue-cultured human microvascular endothelial cells, we have investigated the effects of hypoxic stress on CD105 gene expression. Hypoxia induced a significant increase in membrane-bound and secreted CD105 protein levels. CD105 mRNA and promoter activity were also markedly elevated, the latter returning to the basal level after 16 hours of hypoxic stress. Hypoxia induced cell cycle arrest at the G0/G1 phases and massive cell apoptosis after 24 hours through a reduction in the Bcl-2 to Bax ratio, downregulation of Bcl-X-L and Mcl-1, and upregulation of caspase-3 and caspase-8. The consequence of CD105 upregulation was revealed using an antisense approach and a TUNEL assay. Suppression of CD105 increased cell apoptosis under hypoxic stress in the absence of TGFbeta1. Furthermore, hypoxia and TGFbeta1 synergistically induced apoptosis in the CD105-deficient cells but not in the control cells. We conclude that hypoxia is a potent stimulus for CD105 gene expression in vascular endothelial cells, which in turn attenuates cell apoptosis and thus contributes to angiogenesis.
引用
收藏
页码:2677 / 2685
页数:9
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