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Introduction and Objective: Platelet activation and subsequent cargo secretion play a critical role in thrombus formation and aortic remodeling, factors potentially influencing the growth and rupture of abdominal aortic aneurysms (AAA). Despite the compelling data that platelet activation is associated with AAA and rupture, the underlying mechanisms remain poorly understood. This study hypothesizes that VAMP8, a key element of platelets’ secretory machinery, 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 (n=3131, 213.76 ± 3.46) vs. healthy individuals (n= 6309, 243.18 ± 4.09) suggesting an increase in platelets consumption, potentially in the aneurysmal sack. Thoracic aortic aneurysm and aortic dissection patients also indicated lower platelet count. In vivo , platelets were shown to accumulate at elastin break sites and false lumens of abdominal aortas from 28-day AngII-infused hypercholesteremic mice. To assess the role of platelets, specifically platelet secretion, we utilized VAMP8 null mice. We first validated the platelet secretion defect in these mice and then used RNASeq and proteomics array to define the role of VAMP8 in platelet cargo packaging. Next, VAMP8 -/- or WT hypercholesterolemic male mice fed a Western diet were infused with AngII (1,000 ng/kg/min) for 4 weeks. Our results revealed that VAMP8 -/- mice are protected against AngII-driven aortic rupture. Additionally, aortic ex vivo analysis indicated that the VAMP8 deficiency (n=15, aortic diameter: 0.9 mm ± 0.03) profoundly attenuated AngII-induced AAA compared to control (n=9, aortic diameter: 2.0 mm ± 0.2). Further analysis also indicated a marked reduction in thoracic aortic aneurysm and atherosclerosis development in VAMP8 -\- vs. Control group. Conclusion: Our results elucidate that a deficiency in VAMP8 results in the profound attenuation of aortic aneurysms and atherosclerosis development, introducing a novel paradigm for understanding the impact of platelet cargo secretion in the development of aortopathies.
Mohammadmoradi et al. (Wed,) studied this question.