Loss of arap3 drives a cerebral cavernous malformation-like phenotype in zebrafish via Krit1 interaction and RhoA...

Cerebral cavernous malformations (CCMs) are severe vascular anomalies characterized by abnormal cerebrovascular development, leading to profound structural and functional deficits in the brain. However, the exact underlying mechanisms driving CCM pathogenesis remain incompletely understood. In this study, we identify a zebrafish arap3 mutant that exhibits localized vascular dilation, cerebral hemorrhage, impaired vascular network formation and reduced mural cell coverage - phenotypes that collectively and strikingly recapitulate the key pathological features of clinical CCM. We demonstrate that arap3 is highly enriched in cerebrovascular endothelial cells, and its deficiency severely impairs endothelial cell polarity and overall vascular homeostasis. Mechanistically, arap3 contributes to CCM pathogenesis through the dysregulation of RhoA GTPase activity. Furthermore, we provide compelling evidence physically and functionally linking Arap3 to the CCM signaling complex by demonstrating that Arap3 interacts with Krit1 (CCM1). Our findings establish a crucial framework for understanding the etiology of CCM and present a highly trackable in vivo model for the future discovery of targeted therapeutics.