Abstract WP224: Pharmacological Clearance Of Senescent Cells Prevents Intracranial Aneurysm Rupture

Background: Clinical studies consistently show a strong association between aging and increased risk of intracranial aneurysmal rupture. Aging causes the accumulation of senescent cells that promote chronic inflammation through the senescence-associated secretory phenotype. Since inflammation is emerging as a vital component of the pathophysiology of intracranial aneurysms, the accumulation of senescent cells in the aneurysm wall may play a critical role in the rupture of intracranial aneurysm. We hypothesized that the pharmacological clearance of senescent cells reduces the risk of aneurysmal rupture. We tested this hypothesis using a well-established mouse model with a senescent cell-clearing senolytic drug, ABT263. Methods: We used male C57BL/6J mice and induced intracranial aneurysms by combining an elastase injection and hypertension. We treated mice with either ABT263 (50 mg/kg/day, oral gavage) or a vehicle from one day before aneurysm induction and continued for three weeks. The development of aneurysmal rupture was used as the primary endpoint. We also assessed the effects of ABT263 or vehicle on mRNA expression levels of senescent cell markers (p16 and p21) in cerebral arteries. Results: The pharmacological clearance of senescent cells with ABT263 significantly decreased the rupture rate in mice (P<0.05, Figure A). Furthermore, ABT263 treatment significantly reduced the mRNA expression of p16 and p21 in cerebral arteries (P<0.05, Figure B and C). Conclusion: We demonstrated that pharmacological clearance of senescent cells decreased intracranial aneurysmal rupture. The reduction of rupture rate was associated with the reduction of senescence markers. These findings suggest a link between cellular senescence and aneurysmal rupture. Cellular senescence may be responsible for the age-dependent increase in aneurysm rupture. Senolytic drugs may serve as a novel therapy for preventing aneurysm rupture.