Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor β1 with higher affinity receptors and an activated Alk1 pathway
Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor β1 with higher affinity receptors and an activated Alk1 pathway
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DOI：
10.1074/jbc.m503471200
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发表时间：
2005-07-29
影响因子：
4.8
通讯作者：
Letarte, M
中科院分区：
文献类型：
--
作者：
Pece-Barbara, N;Vera, S;Letarte, M
内皮糖蛋白是内皮细胞中转化生长因子β（TGF β）的辅助受体，对血管发育至关重要。其在血管生成中的关键作用在内皮糖蛋白缺失（Eng（-/-））小鼠胚胎中得到强调，所述小鼠胚胎在妊娠中期（E10.5）死于受损的卵黄囊血管形成。此外，内皮糖蛋白和内皮特异性TGF β I型受体ALK 1的突变与遗传性出血性毛细血管扩张症有关。为了确定内皮糖蛋白在TGF β途径中的作用，我们从Eng（-/-）和Eng（-/-）胚胎（E9.0）中获得鼠内皮细胞系。而Eng（+/ +）细胞仅部分生长受TGF β抑制，Eng（-/-）细胞显示出有效的抗增殖反应。TGF β依赖性Smad 2磷酸化和Smad 2/3易位在Eng（-/-）细胞中未发生变化。相比之下，TGF β处理导致Eng无效细胞中Smad 1/5途径的更快速活化，这在较低的TGF β浓度下是明显的。Eng（-/-）细胞中Smad 1途径活性增强反映在ALK 1依赖性基因（如Id 1、Smad 6和Smad 7）的较高表达中。细胞表面受体分析显示，TGF β I型受体ALK 5（ALK 1功能所需）在Eng（-/-）细胞中增加。TGF β受体复合物数量较少，但显示出较高的结合亲和力。这些结果表明内皮糖蛋白通过调节表面TGF β受体和抑制Smad 1活化来调节内皮细胞中的TGF β信号传导。因此，TGF β受体和下游Smad通路的平衡改变可能是血管发育和稳态缺陷的基础。
Endoglin is an accessory receptor for transforming growth factor beta(TGF beta) in endothelial cells, essential for vascular development. Its pivotal role in angiogenesis is underscored in Endoglin null (Eng(-/-)) murine embryos, which die at mid-gestation (E10.5) from impaired yolk sac vessel formation. Moreover, mutations in endoglin and the endothelial-specific TGF beta type I receptor, ALK1, are linked to hereditary hemorrhagic telangiectasia. To determine the role of endoglin in TGF beta pathways, we derived murine endothelial cell lines from Eng(-/-) and Eng(-/-) embryos (E9.0). Whereas Eng(+/ +) cells were only partially growth inhibited by TGF beta, Eng(-/-) cells displayed a potent anti-proliferative response. TGF beta-dependent Smad2 phosphorylation and Smad2/3 translocation were unchanged in the Eng(-/-) cells. In contrast, TGF beta treatment led to a more rapid activation of the Smad1/5 pathway in Eng null cells that was apparent at lower TGF beta concentrations. Enhanced activity of the Smad1 pathway in Eng(-/-) cells was reflected in higher expression of ALK1-dependent genes such as Id1, Smad6, and Smad7. Analysis of cell surface receptors revealed that the TGF beta type I receptor, ALK5, which is required for ALK1 function, was increased in Eng(-/-) cells. TGF beta receptor complexes were less numerous but displayed a higher binding affinity. These results suggest that endoglin modulates TGF beta signaling in endothelial cells by regulating surface TGF beta receptors and suppressing Smad1 activation. Thus an altered balance in TGF beta receptors and downstream Smad pathways may underlie defects in vascular development and homeostasis.