Cerebral Cavernous Malformation 1/2 complex controls ROCK1 and ROCK2 complementary functions for endothelial integrity

Abstract

Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This cross-talk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in CCM genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions. Our study reveals that CCM proteins directly orchestrate ROCK1 and ROCK2 complementary roles on the mechanics of the endothelium. CCM proteins act as a scaffold promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 produces excessive ROCK1-dependent actin stress fibers and destabilizes intercellular junctions. Silencing of ROCK1 but not ROCK2 restores the adhesive and mechanical homeostasis of CCM1/2-depleted endothelial monolayers and rescues cardiovascular defects of ccm1 mutant zebrafish embryos. Conversely, knocking down of Rock2 but not Rock1 in WT zebrafish embryos generates defects reminiscent of the ccm1 mutant phenotypes. Our study uncovers the role of the CCM complex in controlling ROCK1 and ROCK2 to preserve endothelial integrity and drive heart morphogenesis. Moreover, it identifies solely the ROCK1 isoform as therapeutic target for the CCM disease.