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First published online 13 May 2003
doi: 10.1242/jcs.00470
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Research Article |
1 Department of Pathology, Medical School, University of Manchester and Christie
Hospital, Manchester M13 9PT, UK
2 Department of Biological Sciences, Manchester Metropolitan University,
Manchester, UK
3 University of Manchester Academic Unit of Obstetrics and Gynaecology, St
Mary's Hospital, Manchester M13 0JH, UK
4 Institute Reina Sofia de Investigacion Nefrologica, Department of Physiology
and Pharmacology, Salamanca University, Salamanca, Spain
5 Department of Immunology, Centro de Investigaciones Biologicas, CSIC, 28006
Madrid, Spain
* Author for correspondence (e-mail: mddpscl2{at}fs1.scg.man.ac.uk)
Accepted 7 March 2003
CD105, a marker of endothelial cells, is abundantly expressed in tissues undergoing angiogenesis and is a receptor for transforming growth factorß. 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-XL 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 TGFß1. Furthermore, hypoxia and TGFß1 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.
Key words: Hypoxia, CD105, Endothelial cells, TGFß1, Apoptosis
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