Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial to Mesenchymal Transition
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 &bgr;/p Smad and &bgr; 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.
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