Cerebral cavernous malformations as a disease of vascular permeability: from bench to bedside with caution

Abstract

Tremendous insight into the molecular and genetic pathogenesis of cerebral cavernous malformations (CCMs) has been gained over the past 2 decades. This includes the identification of 3 distinct genes involved in familial CCMs. Still, a number of unanswered questions regarding the process from gene mutation to vascular malformation remain. It is becoming more evident that the disruption of interendothelial junctions and ensuing vascular hyperpermeability play a principal role. The purpose of this review is to summarize the current understanding of CCM genes, associated proteins, and functional pathways. Promising molecular and genetic therapies targeted at identified molecular aberrations are discussed as well.

Fig. 1

Depiction of the current understanding of the CCM pathway. An unidentified ligand binds to a transmembrane receptor named heart of glass (HEG) that interacts with an intracellular protein complex comprised of the CCM proteins. This interaction leads to a number of processes, including the inhibition of a RhoA GTPase, that ultimately result in normal interendothelial cell junctions and vascular integrity.