PROJECT SUMMARY / ABSTRACT Small unruptured intracranial aneurysms (UIAs) (3–7 mm in diameter) have an average annual likelihood of growth (≥1 mm) of 3% per year (range: 7–21% over 2–4 years of follow-up).1-11 Intracranial aneurysms (IA) that enlarge have 12–24 times increased risk of rupture compared to those that do not.1-11 These data compelled the AHA/ASA in their 2015 guidelines to strongly recommend surgical or endovascular treatment of UIAs that enlarge,12 but the need for these expensive invasive procedures, which have associated morbidity and mortality, could be limited if pharmaceutical treatments could be developed to prevent IA growth or rupture. Based on data from a series of studies in humans and animals regarding UIAs, Aspirin has shown to safe, inexpensive, and effective treatment to decrease IA growth and rupture. But do women and men respond equally to ASA? The answer is NO. (A) Our animal study revealed that there are sex-specific differences in the biologic response to ASA and the ability of ASA to reduce the risk of IA rupture in mice.15 (B) We identified effects on expression of 15-PGDH as a potential cause of this phenomenon and reversed these effects by activating this enzyme in female mice and inhibiting it in male mice.15 (C) The finding of sex-specific responses to ASA in mice was confirmed in humans using data from ISUIA cohort, with ASA being 20% more effective in reducing IA rupture in males than females.15 (D) Serum analysis of blood collected from within human IA sacs showed significant elevation of 15-PGDH in males when compared to females, confirming our findings in mice and adding more evidence of sex differential response to ASA and 15- PGDH as potential explanation for this response.23 Our proposal seeks to test these primary hypotheses: (1) activation of 15-PGDH decreases the risk of IA rupture by: a) decreasing the harmful expression of PGE2 and b) converting PGE2 to 15-keto PGE2 which acts as an endogenous agonist of PPAR, which is known to decrease the risk of IA rupture; (2) the effect of 15- keto PGE2 is cell-specific to smooth muscle cells and macrophages. To test these hypotheses, we will perform these two specific aims: Specific Aim 1: Test the hypothesis that activation of 15-PGDH decreases risk of UIA rupture equally in male and female WT mice by (A) decreasing expression of PGE2 and (B) increasing 15-keto PGE2 which acts as an endogenous agonist of PPAR which we showed decreases the risk of IA rupture. Specific Aim 2: Test the hypothesis that the effect of 15-keto PGE2 (final byproduct of 15-PGDH which functionally acts as an endogenous PPAR activator) primarily acts in smooth muscle cells (SMC) and macrophages (MΦ).

PROJECT NARRATIVE Several human observatory studies and pre –clinical date from animal model of cerebral aneurysms strongly suggests that aspirin attenuates the inflammatory process within the wall of these aneurysms resulting in decreased aneurysm rupture; however, aspirin has sex differential response. It is more protective in males than females due in part to 15-PGDH activities. In this proposal, we seek to delineate the mechanistic pathway by which 15-PGDH exerts its protective effect.