Abstract 269: Role Of Sympathetic Nervous System In Abdominal Aortic Aneurysm Pathogenesis

Objective: Abdominal aortic aneurysm (AAA) remains a prevalent and life-threatening disease with no current pharmacologic therapies. This study aims to evaluate the role of the perivascular sympathetic nervous system (SNS) during AAA formation. We hypothesize that dysfunction of sympathetic innervation to the abdominal aortic smooth muscle is crucial to the onset of aortic dilatation and progression of aneurysmal disease. Methods: To generate experimental AAA, ApoE -/- mice (n=5) underwent subcutaneous osmotic pump implantation for continuous Angiotensin II (AngII) infusion. For systemic denervation, ApoE -/- mice underwent serial intraperitoneal injection of 6-hydroxydopamine (6-OHDA) (n=7) or saline control (n=3). Animals were sacrificed at model-specific time points for morphologic, histologic, and immunohistochemical analysis. Combining AngII infusion with 6-OHDA administration is currently underway and anticipated to conclude prior to this meeting. Results: ApoE -/- mouse aortas were harvested after 4 weeks of AngII infusion. Tyrosine hydroxylase (TH), an SNS-specific marker, was utilized to visualize nerve fibers (Figure). Experimental aortic walls demonstrated significantly increased nerve fibers (n=32.3 ± 7.1) and density (154.4 ± 47.2 fibers/mm 2 ) as compared to healthy controls (n=3.7 ± 1.7, 53.5 ± 19.2 fibers/mm 2 ). 6-OHDA administration produced sustained denervation of mesenteric branch arteries through two weeks with evidence of some neural regeneration at 4 weeks. No mortality or weight loss was observed after 6-OHDA administration. Conclusion: Generation of experimental AAA is associated with upregulation of SNS fiber density. 6-OHDA administration confers systemic arterial denervation, though further optimization is warranted. Together, these findings suggest an evolving role of SNS dysregulation in AAA pathogenesis and highlight the need for further investigation as a therapeutic target.