CD105 (Endoglin), Apoptosis, and Stroke
To the Editor:
The recent paper by Zhu et al1 in this journal provides an insight into the possible mechanism of hypoxia-induced upregulation of CD105 (endoglin). The following 3 points are relevant to their paper.
Suitability of Endothelial Cell Culture and Animals as Models for Human Stroke
Lately there has been a major debate regarding the relevance of cell culture/animal models for human stroke in general and for angiogenesis in particular. Some authors maintain that the failure of current therapies for stroke in humans based on the use of animal models is possibly owing to the fact that the pathobiology of human stroke is not mirrored by experimentally-induced stroke in animal models. If true, it would limit the value findings of Zhu et al,1 which are based on the use of murine endothelial cell culture and an in vivo mouse model of focal cerebral ischemia. However, there is strong evidence to discount this possibility. First, CD105 has been found to be highly expressed in the penumbra region of human stroke.2 Second, soluble CD105 levels in plasma have been found to be high in patients with stroke (our unpublished data, 2004). Furthermore, human vascular, like murine, endothelial cells showed an upregulation of CD105 expression when cultured under hypoxic conditions, although there were some notable differences in the 2 studies.1,3
Hypoxia and Apoptosis
Li et al3 reported that hypoxia-induced upregulation of CD105 prevented vascular endothelial cells from undergoing TGF-β–induced cell apoptosis. The overexpression of CD105 in hypoxic cells ameliorated cell apoptosis either with or without TGF-β1, the conclusion being that CD105 functions via TGF-β1 signaling plus another independent pathway, as yet unknown. Since only 1% of CD105 binds to TGF-β, the function of the remaining 99% remains unknown.4 Protection against apoptosis by CD105 could be one of its new functions.
The Mechanism of CD105 Induction
CD105 expression induced by hypoxia has been reported to be due to hypoxia-inducible factor-1α (HIF-1α), which directly binds to the hypoxia response element in the CD105 promoter. It has also been reported that small mothers against decapentaplegic (Smad3) and promoter-specific transcription factor 1 (SP1) interact with HIF to upregulate the expression of CD105.5 Hypoxia is a complicated biological process, and the expression of CD105 regulated by hypoxia is possibly involved in several pathways which may cross-talk (Figure 1). Hypoxic upregulation of gene expression involves extracellular signal-regulated kinase, which is associated with cell survival, as well as p38 and Jun N-terminal kinase (JNK), which are implicated in cell death. Zhu et al demonstrated that hypoxia-induced expression of CD105 was regulated by p38, but the role of JNK remained unresolved. In an attempt to understand the molecular mechanism by which CD105 exerts its effect on angiogenesis by TGF-β signaling, CD105 transfectants were utilized in an in vitro model, wherein overexpression of CD105 antagonised (CAGA)12-luc luciferase activity.6,7 The latter sequence is specific for TGF-β–induced Smad3 signaling. CD105 overexpression reduced serine phosphorylation of Smad3 and its intranuclear translocation and resulted in high phosphorylation of JNK1 that was able to activate c-Jun. The latter is known to inhibit Smad3 transcriptional activity on CAGA sites, suggesting that CD105 blunts Smad3 signaling through JNK1. Figure 1 summarizes the current understanding of this field. Knowledge of CD105 signaling would have practical implications for the discovery of novel therapies in a host of angiogenic diseases.
Zhu Y, Sun Y, Xie L, Jin K, Sheibani N, Greenberg DA. Hypoxic induction of endoglin via mitogen-activated protein kinases in mouse brain microvascular endothelial cells. Stroke. 2003; 34: 2483–2488.
Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994; 25: 1794–1798.
Li C, Issa R, Kumar P, Hampson IN, Lopez-Novoa JM, Bernabeu C, Kumar S. CD105 prevents apoptosis in hypoxic endothelial cells. J Cell Sci. 2003; 116: 2677–2685.
Lastres P, Letamendia A, Zhang H, Rius C, Almendro N, Raab U, Lopez LA, Langa C, Fabra A, Letarte M, Bernabeu C. Endoglin modulates cellular responses to TGF-beta 1. J Cell Biol. 1996; 133: 1109–1121.
Sanchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabeu C. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J Biol Chem. 2002; 277: 43799–43808.
Guo B, Slevin M, Li C, Parameshwar S, Liu D, Kumar P, Bernabeu C, Kumar S. CD105 inhibits transforming growth factor-beta SMAD3 signalling. Anti Cancer Res. In press.
Guo B, Rooney P, Slevin M, Li C, Parameshwar S, Li D, Kumar P, Bernabeu C, Kumar S. Overexpression of CD105 in rat myoblasts: role of CD105 in cell attachment, spreading, and survival. Int J Cancer. In press.