Abstract 4358384: Nitro-oleic acid (CXA-10) prevents cerebral aneurysm formation via endothelial PPARδ activation

Cerebral aneurysms (CA) affect 2-3% of the adult population and remain a potentially lethal disease as they can rupture producing subarachnoid hemorrhage (SAH). Endothelial dysfunction is highlighted as an early marker of vascular abnormality preceding CA formation, but the molecular events behind this alteration remain unclear. Surgical interventions remain the primary treatment for managing existing aneurysms and about 10-15% of patients may require retreatment due to aneurysm regrowth or coil compaction. Given the potentially lethal complications of CA, there is a critical need to establish pharmacological therapy for CA which does not presently exist. 10-nitro-9(E)-octadec-9-enoic acid (CXA-10), a synthetic nitro-fatty acid, is an emerging therapeutic agent for enhancing endothelial cell function and preventing vascular diseases. It has advanced to Phase 2 clinical trials and can activate PPAR-δ, a nuclear receptor involved in regulating several aspects of vascular homeostasis. Hence, we hypothesize that CXA-10, through PPARδ activation, enhances endothelial integrity, controls inflammation, and supports vascular repair to prevent CA formation. For this study, a well-established elastase-induced mouse model of CA was used and animals were treated with two different doses of CXA-10 (5 and 10 mg/kg/day). Blood pressure was monitored using the tail-cuff method. Single-cell RNA sequencing, flow cytometry, and western blot were utilized to measure gene and protein expression. To further investigate the effect of CXA-10 on endothelial Pparδ activation, brain endothelial cell culture was used. Preliminary findings revealed a significant reduction in the number of CA formation with the higher dose of CXA-10 (p<0.001). No significant differences were observed in blood pressure or rupture rate across treatment groups. CXA-10 treatment also upregulated PPARδ activation (p=0.013) in CA-induced endothelial cells and rescued its protein expression in the Circle of Willis vessels. In vitro, CXA-10 significantly upregulated the protein expression of Pparδ and major tight junction proteins in cultured brain microvascular endothelial cells (BMECs). CXA-10 demonstrated a dose-dependent effect against CA formation, likely through the endothelial-protective effect of PPARδ receptor activation. Further research is warranted to provide insights into its mechanism of action and optimize clinical applications.