Cerebral cavernous malformations (CCM) are lesions affecting brain capillaries that appear with a mulberry-like morphology. This shape results from the enlarged and tangled microvessels having defective endothelial cell junctions, few surrounding pericytes and dense extracellular collagen-rich matrix. Three genes KRIT1, CCM2 and PDCD10 are linked to disease onset. However, a variable percentage of patients harbour no mutations at these loci, encouraging hypothesis of further genetic factors involved in CCM pathogenesis. Here we present data obtained by transcriptome analysis on endothelial cells isolated by CCM specimens, with the aim to identify dysregulated pathways involved in lesion onset. Lesions belonged to two patients carried neither germline nor somatic mutations at the three CCM genes. By comparison with Human brain microvascular endothelial cells (HBMECs) expression profile, we identified 1325 differentially expressed genes (Bonferroni pValue <0.05) common for the two samples. Functional enrichment analysis clustered these genes in 80 terms related to neuroinflammation, extra-cellular matrix remodelling, cell junction impairment, reactive oxygen species metabolism. In addition, CCM genes expression values resulted slightly altered in only one of the two CCM endothelial cell samples when compared to HBMECs, suggesting as further genetic factors can contribute to CCM development. Following expression analysis, we suggests that the molecular shift from canonical to non-canonical Wnt pathway might be a key event in CCM pathogenesis. Moreover, our results provide novel potential genetic targets to investigate for the development of more selective therapies.

脑海绵状畸形（CCM）是影响大脑毛细血管的病变，表现为桑树样形态。这种形状是由于微血管的扩大和缠结造成的，这些微血管具有缺陷的内皮细胞连接，很少的周围周细胞和致密的细胞外胶原富集基质。三种基因KRIT1，CCM2和PDCD10与疾病发作有关。但是，可变百分比的患者在这些基因座处没有突变，这鼓励了有关CCM发病机理的其他遗传因素的假说。在这里，我们介绍通过CCM标本分离的内皮细胞的转录组分析获得的数据，目的是确定参与病变发作的失调途径。属于两个患者的病变在三个CCM基因上均未携带种系突变或体细胞突变。通过与人脑微血管内皮细胞（HBMEC）表达谱进行比较，我们确定了两个样品共有的1325个差异表达基因（Bonferroni pValue <0.05）。功能富集分析将这些基因聚集在与神经炎症，细胞外基质重塑，细胞连接障碍，活性氧代谢相关的80个术语中。此外，与HBMEC相比，仅在两个CCM内皮细胞样品中的一个中，CCM基因表达值的结果稍有改变，表明进一步的遗传因素可促进CCM的发展。通过表达分析后，我们建议分子从经典Wnt途径向非经典Wnt途径的转变可能是CCM发病机制中的关键事件。此外，我们的结果提供了新的潜在的遗传靶点，以研究更多选择性疗法的发展。我们认为分子从经典Wnt途径向非经典Wnt途径的转变可能是CCM发病机制中的关键事件。此外，我们的结果提供了新的潜在的遗传靶点，以研究更多选择性疗法的发展。我们认为分子从经典Wnt途径向非经典Wnt途径的转变可能是CCM发病机制中的关键事件。此外，我们的结果提供了新的潜在的遗传靶点，以研究更多选择性疗法的发展。