Flow induced-endothelial phenotypic transition contributes to Intracranial Aneurysm

Rupture of intracranial aneurysms (IAs) represents a life-threatening cerebrovascular event associated with high morbidity and mortality. Elucidating the pathological mechanisms driving IA initiation and progression is critical for developing an effective therapeutic strategy. Endothelial cell (EC) dysfunction is known to contribute to IA pathogenesis. Hemodynamic force— particularly fluid shear stress (FSS) are well-established mediators of IA pathogenesis, yet the mechanisms by which FSS triggers endothelial injury remain incompletely understood. In this study, single-cell sequencing of human revealed that endothelial-to-mesenchymal transition (EndMT) as a hallmark feature of early-stage IA formation, whereas EndMT was markedly attenuated in ruptured aneurysms. Using a mouse IA model and an in vitro parallel-plate flow chamber system, we demonstrated that exposure to high laminar FSS (HSS) promotes EndMT in endothelial cells, concomitant with actin cytoskeletal reorganization and nuclear translocation of Yes-associated protein (YAP). In contrast, under low or vortex flow (VSS) conditions characteristic of advanced IA stages, endothelial cells undergo phenotypic reversion—evidenced by reduced expression of cytoskeletal proteins and cytoplasmic sequestration of YAP. Notably, endothelial inflammation escalates progressively throughout IA development and contributes directly to sustained endothelial dysfunction. Pharmacological inhibition of actin polymerization effectively suppressed EndMT in the early stage but failed to restore endothelial integrity during the late stage. Collectively, these findings identify FSS–cytoskeleton–YAP–EndMT axis as a stage-specific, druggable pathway with translational potential for early intervention in intracranial aneurysm disease.