Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition
Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition
复制标题
DOI：
10.1161/strokeaha.115.011867
复制
发表时间：
2016-03-01
期刊：
影响因子：
8.3
通讯作者：
Lampugnani, Maria Grazia
中科院分区：
文献类型：
--
作者：
Bravi, Luca;Malinverno, Matteo;Lampugnani, Maria Grazia
背景和目的-脑海绵状血管畸形（CCM）的特征是中枢神经系统的多腔血管畸形，可引起神经系统症状和脑损害。大约20%的CCM患者具有遗传形式的疾病，在3个基因CCM 1、CCM 2和CCM 3中的任何一个中具有普遍的功能丧失突变。其余患者发生散发性血管病变，在组织学上与遗传形式的血管病变相似，并且可能由脑血管系统中CCM基因的双等位基因获得性突变介导。然而，在散发性患者的CCM病变的内皮细胞的分子表型特征仍然很差的描述。这些信息对于靶向治疗是至关重要的。Methods-我们使用免疫荧光显微镜和免疫组化来分析与人类家族性海绵状血管瘤平行的散发性CCM患者的海绵状血管瘤中内皮-间充质转化标志物的表达作为参考对照。在散发性患者的病变中经历内皮细胞向间充质细胞的转化。这种内皮细胞表型的转换仅在遗传性CCM患者和该疾病的鼠模型中描述。此外，TGF-β/β-Smad-和β-连环蛋白依赖的信号通路似乎激活在散发性海绵状血管瘤在familial ones. Conclusions，我们的研究结果支持使用共同的治疗策略，为散发性和遗传性CCM畸形。
Background and Purpose-Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy.Methods-We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control.Results-We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-beta/p-Smad- and beta-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones.Conclusions-Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.