Transcriptome analysis provides new molecular signatures in sporadic Cerebral Cavernous Malformation endothelial cells.

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.