ARHGEF17 Deficiency Induces Endothelial Dysfunction and Intracranial Aneurysm Formation via RhoA/ROCK2/MLC Signaling Pathway

BACKGROUND: Genetic susceptibility critically contributes to intracranial aneurysm (IA) formation and rupture, but the mechanisms linking genetic variants to vascular dysfunction remain unclear. ARHGEF17, a Rho guanine nucleotide exchange factor regulating RhoA activation and cytoskeletal dynamics, has been identified as a potential IA risk gene. METHODS: CRISPR-Cas9-generated ARHGEF17-/- mice and morpholino-based ARHGEF17-deficient zebrafish were used to assess in vivo vascular effects. An elastase/DOCA-induced IA model evaluated aneurysm formation, rupture, and survival. Vascular remodeling of the Circle of Willis was analyzed by histology and immunofluorescence. Endothelial function was examined in HUVECs with lentiviral ARHGEF17 knockdown. Activation of RhoA/ROCK2/MLC signaling was assessed by G-LISA and Western blotting, with Y-27632 used to test ROCK2 dependence. RESULTS: ARHGEF17 deficiency increased IA incidence and rupture, accompanied by elastic fiber fragmentation, VSMC dedifferentiation, and inflammatory activation. Zebrafish lacking ARHGEF17 exhibited intracranial hemorrhage and vascular instability. In endothelial cells, ARHGEF17 silencing impaired proliferation, migration, angiogenesis, and barrier integrity while activating the RhoA/ROCK2/MLC pathway. ROCK inhibition with Y-27632 restored endothelial function and cytoskeletal organization. CONCLUSIONS: ARHGEF17 maintains cerebrovascular integrity by regulating RhoA/ROCK2/MLC-mediated cytoskeletal dynamics. Its deficiency drives endothelial dysfunction, vascular inflammation, and IA formation, while ROCK inhibition reverses these effects, identifying the RhoA/ROCK2 axis as a therapeutic target for ARHGEF17 mutation-associated IAs.