Aspirin Decreases Risk of Aneurysm Formation & Rupture in Male Mice More Than Females via the Effect of 15-PGDH and EP2

Introduction: Inflammation has been identified as a key factor in the rupture of Intracranial aneurysms (IAs). Acetylsalicylic acid (ASA) has shown promise in reducing the risk of IA rupture, with previous research suggesting a more pronounced effect in males.

Methods: Adult C57BL/6J mice (n=301, 9-10 weeks old) and 15-Pgdh knockout (KO) mice were used to model IA formation and rupture through elastase injection and Angiotensin II infusion. Mice were randomized to receive ASA (5 mg/kg/d), 15-PGDH activator (CDDO-Me), 15-keto PGE2, or EP2 antagonist (PF044), with treatments continuing for 21 days. mRNA expression of 15-Pgdh, Keap1, and other markers was analyzed using qRT-PCR.

Results: Compared to controls, ASA significantly reduced IA formation (60% vs. 87%, p=0.01) and rupture (43% vs. 68%, p=0.04) in WT mice. When stratified by sex, ASA decreased the risk of IA formation in males (40% vs. 86% in control, p=0.01) and rupture (53% vs. 90% in control, p=0.01) but did not show a statistically significant effect in females (formation: 80% vs. 90%, p=0.4; rupture: 33% vs. 60%, p=0.2). In female mice, the addition of 15-PGDH activator (CDDO-Me) with ASA significantly reduced rupture risk (33% vs. 73% in ASA-only group, p< 0.01), while 15-PGDH inhibition in males reversed the protective effect of ASA (60% rupture with inhibitor vs. 20% with ASA alone, p=0.04). In 15-Pgdh knockout mice, the administration of 15-keto PGE2 significantly decreased IA rupture risk in both sexes (male: 30% vs. 60% in control, p=0.045; female: 43% vs. 73% in control, p=0.04), without affecting formation rates. EP2 receptor blockade (PF044) in males reduced IA rupture risk by 80% (8% vs. 40% in controls, p=0.02), whereas no significant reduction was observed in females (24% vs. 28%, p=1).

Conclusion : Our findings suggest that the sex differential effect of ASA in decreasing risk of aneurysm formation and rupture is due to sex difference of 15-PGDH/15-Keto PGE2/ EP2. Targeting these molecules may represent a promising sex-specific therapeutic strategy for reducing the risk of aneurysmal SAH.