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EndMT contributes to the onset and progression of cerebral cavernous malformations

机译：EndMT有助于脑海绵状畸形的发生和发展

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摘要

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 Can 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 Ccml gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM 1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-β (TGF-β) and bone mor-phogenetic 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 CCM 1-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.
机译：脑海绵状畸形（CCM）是一种血管发育不良，主要位于大脑内，影响多达0.5％的人口。 CCM病变是由血管增大和不规则血管形成的，通常会导致脑出血。 CCM是由三个基因之一的功能丧失突变引起的，这三个基因即CCM1（也称为KRIT1），CCM2（OSM）和CCM3（PDCD10），并且以散发和家族形式出现。最近的研究已经调查了CCM中血管发育异常和脆弱的原因，但是这种三元复合物的体内功能仍不清楚。小鼠内皮中三个Can基因中任何一个的产后缺失都会导致严重的表型，其特征是多个脑血管畸形，与人类CCM病变明显相似。内皮到间充质的过渡（EndMT）已被描述在不同的病理学中，它被定义为通过内皮获得间充质和干细胞样特征。在这里，我们显示了小鼠Ccml基因的内皮特异性破坏会诱导EndMT，这有助于血管畸形的发展。 CCM 1切除的内皮细胞中的EndMT由内源性BMP6的上调介导，而内源性BMP6则又激活了转化生长因子-β（TGF-β）和骨形态发生蛋白（BMP）信号通路。 TGF-β和BMP途径的抑制剂可在体内和体外阻止EndMT，并减少CCM1缺陷小鼠的血管病变数量和大小。因此，增加的TGF-β和BMP信号传导以及随之而来的CCM 1无效内皮细胞的EndMT，是CCM疾病发作和发展中的关键事件。这些研究为这种严重的，至今无法治愈的病理提供了新的治疗机会。

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  • 来源
    《Nature》 |2013年第7455期|492-496|共5页
  • 作者

    Luigi Maddaluno; Noemi Rudini; Roberto Cuttano; Luca Bravi; Costanza Giampietro; Monica Corada; Luca Ferrarini; Fabrizio Orsenigo; Eleanna Papa; Gwenola Boulday; Elisabeth Tournier-Lasserve; Franchise Chapon; Cristina Richichi; Saverio Francesco Retta; Maria Grazia Lampugnani; Elisabetta Dejana;

  • 作者单位

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.;

    INSERM, UMR-S740, F-75010 Paris, France, Universite Paris Diderot, Sorbonne Paris Cite, Genetique des Maladies Vasculaires UMR-S740, F-75010 Paris, France.;

    INSERM, UMR-S740, F-75010 Paris, France, Universite Paris Diderot, Sorbonne Paris Cite, Genetique des Maladies Vasculaires UMR-S740, F-75010 Paris, France, AP-HP, Groupe Hospitaller Saint-Louis Lariboisiere-Fernand-Widal, F-75010 Paris, France.;

    Department of Pathology, Centre Hospitaller Universitaire, Avenue Cote de Nacre, 14032 Caen, France.;

    IEO - European Institute of Oncology, 20139 Milan, Italy.;

    CCM Italia - Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy.;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy, Mario Negri Institute of Pharmacological Research, 20156 Milan, Italy,;

    FOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy, Department of Biosciences, University of Milan, 20133 Milan, Italy;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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