Endothelial Cell–Pericyte Interactions in the Pathogenesis of Cerebral Cavernous Malformations (CCMs)

Abstract

Cerebral cavernous malformations (CCMs), consisting of multiple, dilated capillary channels formed by a single layer of endothelium and lacking parenchymal cells, are exclusively to the brain. Patients with inherited autosomal-dominant CCMs carry loss-of-function mutations in one of three genes: CCM1, CCM2, and CCM3. It is not known why CCM lesions are confined to brain vasculature despite the ubiquitous expression of CCM proteins in all tissues, and whether cell types other than endothelial cells (ECs) contribute to CCM lesion formation. The prevailing view is that the primary defects in CCMs in humans are EC-intrinsic, such that EC-specific deletion of any one of the three genes in mice results in similar CCM lesions. An unexpected finding is that Ccm3 deletion in pericytes (PCs) also induces CCM lesions. CCM3 deletion in ECs or PCs destabilizes PC–EC associations, highlighting the importance of these interactions in CCM formation.