Abstract 4363114: VAMP8 Dependent Platelet Secretion Drives Aortic Remodeling and Aneurysm Formation Through Platelet Reprogramming

Background: Platelets are emerging as active contributors to vascular pathology through the regulated release of granule-stored bioactive cargo. While platelet activation has been associated with abdominal aortic aneurysm (AAA) progression, the mechanistic contribution of platelet secretion to aneurysm formation remains incompletely understood. Here, we investigate the role of VAMP8, the primary v-SNARE mediating platelet granule exocytosis, in AAA pathogenesis. Methods and Results: In a hypercholesterolemic, AngII-infused mouse model, we observed significant platelet consumption and accumulation within aneurysmal tissue, particularly at sites of elastin degradation and false lumen formation. Bulk RNA sequencing of washed platelets following 5-day AngII infusion revealed rapid transcriptomic reprogramming toward a hyperactive, pro-inflammatory state. Parallel transcriptomic profiling of suprarenal aortic tissue demonstrated synchronous enrichment in extracellular matrix (ECM) remodeling, inflammatory activation, and platelet-related signaling pathways, establishing a coordinated “platelet–aorta axis” in early disease. VAMP8 -/- mice, which had defective thrombosis, were protected against AngII-induced AAA and rupture. In contrast, NBEAL2 -/- mice, which lack α-granule content, exhibited early rupture and high mortality, underscoring a biphasic and context-dependent role for platelet secretion. VAMP8 -/- mice maintained normal lipid levels and blood pressure, and displayed reduced en face atherosclerotic burden, suggesting additional protection from early atherogenesis. Transcriptomic profiling revealed that VAMP8 deficiency reprogrammed both platelet and aortic gene expression under basal conditions and attenuated early aortic remodeling following AngII infusion, as evidenced by downregulation of ECM-degrading enzymes and inflammatory mediators. Conclusion: VAMP8-dependent platelet granule release drives inflammatory vascular remodeling in AAA and atherosclerosis. Its targeted disruption attenuates pathology without impairing baseline hemostasis, defining platelet secretion as a potential therapeutic target in aortopathies.