CCM scaffolds at the frontier of biomechanics: their roles in vascular physiology and disease

Abstract Cerebral cavernous malformation (CCM) is a genetic vascular disorder arising from endothelial dysfunction, affecting the microvasculature of the central nervous system. Patients with mutations in any of three CCM genes may suffer from neurological deficits and even hemorrhagic stroke. The three CCM proteins are structurally unrelated and assemble into the CCM complex that forms scaffolds associated with junctional complexes and the actomyosin cytoskeleton. Recent work points to a dual role of the CCM complex in structural scaffolding and mechanosensitive signal transduction. In this review, we highlight recent advances examining the CCM complex’s role in organizing various multi-protein interactions and facilitating mechanosensitive signaling that regulates endothelial cell behavior. Importantly, accumulating evidence emphasizes the impact of hemodynamic forces on CCM signaling, pointing to distinct mechanisms in arterial versus venous vessels. Surprisingly, the loss of CCM proteins has vasoprotective effects in arteries but pathological effects in veins and small capillaries. Understanding CCM scaffolds that integrate structural support with mechanosensitive signaling is fundamental to deciphering the molecular mechanisms that underlie physiological versus pathological outcomes within the vasculature. This knowledge advances the development of targeted therapeutic strategies aimed at restoring endothelial integrity and normal vascular function, particularly by modulating signaling pathways influenced by hemodynamic forces.