EndMT contributes to the onset and progression of cerebral cavernous malformations
EndMT contributes to the onset and progression of cerebral cavernous malformations
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DOI：
10.1038/nature12207
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发表时间：
2013-06-27
期刊：
影响因子：
64.8
通讯作者：
Dejana, Elisabetta
中科院分区：
文献类型：
--
作者：
Maddaluno, Luigi;Rudini, Noemi;Dejana, Elisabetta
脑海绵状血管畸形(CCM)是一种血管发育不良，主要局限于脑内，影响高达0.5%的人口。CCM病变是由增大和不规则的血管形成的，这些血管经常导致脑出血。CCM是由CCM1(也称为KRIT1)、CCM2(OSM)和CCM3(PDCD10)三个基因之一的功能丧失突变引起的，以散发性和家族性形式发生(1)。最近的研究(2-7)已经探讨了CCM中血管异常增生和脆性的原因，但这种三元复合体的体内功能仍不清楚(8)。出生后，小鼠内皮细胞中三个CCM基因中的任何一个的缺失都会导致严重的表型，其特征是多发性脑血管畸形，与人类CCM病变非常相似(9)。内皮-间充质转化(EndMT)在不同的病理机制中被描述，它被定义为内皮获得间充质和干细胞样特性(10-12)。在这里，我们证明了Ccm1基因在小鼠体内的内皮特异性破坏诱导了EndMT，这有助于血管畸形的发展。CCM1损毁内皮细胞中的EndMT是由内源性Bmp6上调介导的，内源性Bmp6进而激活转化生长因子-β(TGF-β)和骨形态发生蛋白(BMP)信号通路。转化生长因子-β和骨形态发生蛋白途径的抑制剂在体外和体内均可预防EndMT，并减少CCM1缺陷小鼠的血管病变的数量和大小。因此，转化生长因子-β和骨形态发生蛋白信号的增加，以及随之而来的CCM1缺失的内皮细胞的EndMT，是CCM疾病发生和发展的关键事件。这些研究为这种严重的、迄今无法治愈的病理提供了新的治疗机会。
Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10), and occurs in both sporadic and familial forms(1). Recent studies(2-7) have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear(8). Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions(9). Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell-like characteristics by the endothelium(10-12). Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-beta and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-beta and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology.