β1 activation upon loss in CCM1 or 2 drives a loop between endothelial cell contractility and ECM with deleterious effect on cell–cell junctions. In a quiescent vessel, ICAP-1 maintains low β1 integrin activation. Endothelial cells are well joined and VE-cadherin adherens junctions are stabilized by a cytoplasmic adaptor complex that recruits junctional actomyosin cytoskeleton. Upon CCM1 or CCM2 depletion, ICAP-1 protein is destabilized and lost. β1 integrin is activated and activates in turn RhoA/ROCK-dependent actin stress fiber formation. Increased β1 integrin activation and cell contractility result in aberrant remodeling of ECM in linear and parallel fibers onto which cells spread and flatten. A self-sustaining mechanical loop is initiated that increases intra- and external tensions destabilizing cell–cell junctions.