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首页> 外文期刊>Development >Defective paracrine signalling by TGF{beta} in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia.
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Defective paracrine signalling by TGF{beta} in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia.

机译：在内皮糖蛋白突变小鼠的卵黄囊脉管系统中，TGFβ引起的旁分泌缺陷信号是一种遗传性出血性毛细血管扩张的范例。

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Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder in humans that is characterised by multisystemic vascular dyplasia and recurrent haemorrhage. Germline mutations in one of two different genes, endoglin or ALK1 can cause HHT. Both are members of the transforming growth factor (TGF) beta receptor family of proteins, and are expressed primarily on the surface of endothelial cells (ECs). Mice that lack endoglin or activin receptor like kinase (ALK) 1 die at mid-gestation as a result of defects in the yolk sac vasculature. Here, we have analyzed TGFbetasignalling in yolk sacs from endoglin knockout mice and from mice with endothelial-specific deletion of the TGFbeta type II receptor (TbetaRII) or ALK5. We show that TGFbeta/ALK5 signalling from endothelial cells to adjacent mesothelial cells is defective in these mice, as evidenced by reduced phosphorylation of Smad2. This results in the failure of vascular smooth muscle cells to differentiate and associate with endothelial cells so that blood vessels remain fragile and become dilated. Phosphorylation of Smad2 and differentiation of smooth muscle can be rescued by culture of the yolk sac with exogenous TGFbeta1. Our data show that disruption of TGFbetasignalling in vascular endothelial cells results in reduced availability of TGFbeta1 protein to promote recruitment and differentiation of smooth muscle cells, and provide a possible explanation for weak vessel walls associated with HHT.
机译：遗传性出血性毛细血管扩张症（HHT）是人类的一种常染色体显性遗传疾病，其特征是多系统血管增生和复发性出血。内皮糖蛋白或ALK1这两种不同基因之一的种系突变可引起HHT。两者都是蛋白质的转化生长因子（TGF）β受体家族的成员，并且主要在内皮细胞（EC）的表面表达。缺乏内皮糖蛋白或激活素受体样激酶（ALK）1的小鼠在妊娠中期死于卵黄囊脉管系统的缺陷。在这里，我们分析了内皮糖蛋白敲除小鼠和具有TGFbeta II型受体（TbetaRII）或ALK5内皮特异性缺失的小鼠卵黄囊中的TGFbeta信号转导。我们表明从这些小鼠的内皮细胞到相邻间皮细胞的TGFbeta / ALK5信号是有缺陷的，如Smad2磷酸化减少所证明。这导致血管平滑肌细胞无法分化并与内皮细胞缔合，从而使血管保持脆弱并扩张。 Smad2的磷酸化和平滑肌的分化可以通过用外源TGFbeta1培养卵黄囊来挽救。我们的数据表明，血管内皮细胞中TGFbeta信号转导的破坏导致TGFbeta1蛋白的可用性降低，从而促进平滑肌细胞的募集和分化，并为与HHT相关的血管壁薄弱提供了可能的解释。

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