CD105 prevents apoptosis in hypoxic endothelial cells

Abstract

CD105, a marker of endothelial cells, is abundantly expressed in tissues undergoing angiogenesis and is a receptor for transforming growth factorβ. 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 TGFβ1. Furthermore,hypoxia and TGFβ1 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.

Antiapoptotic action of hypoxia-inducible factor-1α in human endothelial cells

“…35 In this respect, it is worth noting that HIF-1a can mediate crosstalk between hypoxia and glucose metabolism via glucose response elements. 36,37 Since a significant proportion of transfected HUVECs did not manifest evidence of apoptotic changes by TUNEL assay and activated caspase-3 immunostaining after A/R in the current study, it is probable that other antiapoptotic proteins distinct from HIF-1a may also have conferred some cytoprotection against anoxic stress, as has been shown with respect to CD105 38 and Mcl-1. 39 In summary, we have employed RNAi targeting the HIF-1a gene in primary cultured HUVECs and have demonstrated the role of HIF-1a as an antiapoptotic protein in a model of anoxic stress.…”

Endothelial cell survival during angiogenesis requires the pro-survival protein MCL1

“…Several stimuli have been reported to promote EC apoptosis through downregulation of MCL1 in vitro. These include hypoxia, 25,26 suppression of ERK 27 and Rho inhibition. 28 Conversely, the S1P receptor agonist FTY720P was reported to delay apoptosis in serum-starved HUVEC by upregulating MCL1.…”

TGF-β signaling in vascular biology and dysfunction

“…ECs derived from Eng-/-embryos were unable to proliferate in culture, displayed reduced migration, VEGF secretion and eNOS expression [49,52]. Interestingly, up-regulation of endoglin protects ECs from the apoptotic action of TGF-β1 [53]. Endoglin was recently shown to interact via its Cterminal PDZ binding motif with the scaffolding protein GIPC, which promotes endoglin cell surface retention [54].…”