Abstract WMP36: Inhibition of the Endothelial Shear Stress Sensor, P2x4 Purinoceptor Drastically Reduces Cerebral Aneurysm Formation

Abstract

Background and purpose: Although the assumption that wall shear stress-related hemodynamics is closely involved in cerebral aneurysm formation is now widely accepted, direct evidence still remains to be presented. Here, we examine a role of shear stress in cerebral aneurysm development, focused on a vascular endothelial shear sensor, P2X4 purinoceptor. Methods: P2X4 knockout mice and wild type mice were subjected to cerebral aneurysm-generating surgery with ligation of unilateral common carotid artery and renal hypertension. Damage to the internal elastic lamina, early phase aneurysm development, and the incidence of aneurysm induction were examined by light microscope. The expression of biochemical contributors to aneurysm formation was immunohistochemically examined. Additionally, the P2X4 purinoceptor inhibitor, paroxetine (10mg/kg/day) was administered to Sprague-Dawley rats after aneurysm-inducing surgery, and the incidence of aneurysm formation was examined. Results: Damage to the internal elastic lamina and the frequency of CA induction were significantly diminished in P2X4 knockout mice compared to control wild-type mice after CA-inducing surgery ( p =0.027 and 0.018, respectively). Expression levels of known contributors to aneurysm formation, iNOS, MCP-1, cathepsin L, and COX-2, were immunohistochemically weakened in P2X4 KO mice compared to wild-type mice. Moreover, paroxetine significantly attenuated the incidence of induced aneurysms in rats ( p =0.031). Conclusions: Disruption of the endothelial shear stress sensor, P2X4 purinoceptor drastically reduces cerebral aneurysm formation, suggesting that shear stress-related hemodynamics initiates cerebral aneurysm formation. The P2X4 purinoceptor inhibitor paroxetine, which is also prescribed to human as an antidepressant, may be a potential clinical prophylactic agent against cerebral aneurysm formation.