Abstract Body (Do not enter title and authors here): Introduction and Objective: As vascular sentries, platelets, and their ability to release a host of bioactive molecules, are critical for vascular homeostasis as well as hemostasis. Despite data linking platelet activation to abdominal aortic aneurysms (AAA) and rupture, the underlying mechanisms remain poorly understood. This study addresses the hypothesis that VAMP8, the primary v-SNARE controlling platelet exocytosis, significantly contributes to AAA formation.
Approach and Results: A retrospective, single-center, multiple comparisons study of adult aneurysmal patients admitted to UKHealthCare between 2004 and 2023 revealed a significantly lower platelet count in AAA patients than in healthy individuals. These results were also observed in experimental aneurysm models using an AngII-infused hypercholesterolemic mouse model, suggesting increased platelet consumption. Our results indicated a noticeable accumulation of platelets at elastin break sites and false lumen formation in the abdominal aortas of aneurysmal mice. The platelet accumulation showed significant colocalization with VAMP8, alongside a marked upregulation of VAMP8 in the thrombus segments of the aneurysmal tissue compared to the control. WT and VAMP8-/- mice were infused with AngII (1,000 ng/kg/min) or saline two weeks post PCSK9 AAV infection for 28 days using subcutaneously implanted Alzet mini-osmotic pumps. Our results revealed that VAMP8-/- mice are protected against AngII-driven aortic rupture. Both in vivo and ex vivo aortic diameter analysis indicated that VAMP8 deficiency profoundly attenuated AngII-induced AAA compared to controls. Bulk RNA-seq analysis on washed platelets isolated from VAMP8-/- compared to WT mice revealed distinct transcriptomic profiles with significant enrichment in pathways related to aortic remodeling and aneurysm pathogenesis. Further, RNA-seq analysis of suprarenal aortas (5-day AngII infusion) showed that VAMP8 deficiency significantly reduced extracellular matrix degradation and increased aortic wall stability, as observed by the downregulation of matrix metalloproteinases (MMPs) and the upregulation of collagen synthesis genes.
Conclusion: VAMP8 deficiency results in the profound attenuation of aortic aneurysms, potentially via enhanced ECM stability, introducing a novel paradigm for understanding the impact of platelet cargo secretion in aortopathies.