Endothelial cell disease: emerging knowledge from cerebral cavernous malformations.

Abstract

Endothelial cells dysfunctions are crucial determinants of several human diseases. We review here the most recent reports on endothelial cell defects in cerebral cavernous malformations (CCMs), particularly focusing on adherens junctions. CCM is a vascular disease that affects specifically the venous microvessels of the central nervous system and which is caused by loss-of-function mutation in any one of the three CCM genes (CCM1, 2 or 3) in endothelial cells. The phenotypic result of these mutations are focal vascular malformations that are permeable and fragile causing neurological symptoms and occasionally haemorrhagic stroke. CCM is still an incurable disease, as no pharmacological treatment is available, besides surgery. The definition of the molecular alterations ensuing loss of function mutation of CCM genes is contributing to orientate the testing of targeted pharmacological tools.Several signalling pathways are altered in the three genotypes in a similar way and concur in the acquisition of mesenchymal markers in endothelial cells. However, also genotype-specific defects are reported, in particular for the CCM1 and CCM3 mutation. Besides the specific CCM disease, the characterization of endothelial alterations in CCM has the potentiality to shed light on basic molecular regulations as the acquisition and maintenance of organ and vascular site specificity of endothelial cells.