IFOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
Nature. 2013 Jun 27;498(7455):492-6. doi: 10.1038/nature12207. Epub 2013 Jun 9.
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. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. 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. 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. 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-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-β 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-β 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.
脑静脉血管畸形（cerebral cavernous malformation，CCM）是一种血管发育不良，主要局限于大脑，影响 0.5%的人类人群。CCM 病变由扩大和不规则的血管形成，这些血管通常导致脑内出血。CCM 是由三个基因之一的功能丧失突变引起的，这三个基因分别是 CCM1（也称为 KRIT1）、CCM2（OSM）和 CCM3（PDCD10），并以散发和家族形式发生。最近的研究调查了 CCM 血管发育不良和脆弱性的原因，但这个三元复合物的体内功能仍不清楚。在小鼠内皮细胞中敲除任何一个 Ccm 基因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。内皮细胞向间充质细胞的转化（endothelial-to-mesenchymal transition，EndMT）已在不同的病理中被描述，其定义为内皮细胞获得间充质和干细胞样特征。在这里，我们表明，在小鼠中内皮细胞特异性敲除 Ccm1 基因会诱导 EndMT，这有助于血管畸形的发展。在 CCM1 缺失的内皮细胞中，EndMT 是由内源性 BMP6 的上调介导的，BMP6 反过来又激活转化生长因子-β（transforming growth factor-β，TGF-β）和骨形态发生蛋白（bone morphogenetic protein，BMP）信号通路。TGF-β和 BMP 通路的抑制剂可在体外和体内阻止 EndMT 的发生，并减少 CCM1 缺陷型小鼠中血管病变的数量和大小。因此，TGF-β和 BMP 信号的增加，以及由此导致的 CCM1 缺失内皮细胞的 EndMT，是 CCM 疾病发病和进展的关键事件。这些研究为这种严重的、迄今为止无法治愈的疾病提供了新的治疗机会。
