Abstract
BACKGROUND: 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, contributes to AAA formation. METHODS AND RESULTS: In an AngII-infused hypercholesterolemic mouse model, we observed significant platelet consumption, indicated by decreased platelet counts at both acute (5-day) and chronic (28-day) time points. Platelets accumulated at sites of elastin degradation and within false lumens of the abdominal aorta after 28 days of AngII infusion. Bulk RNA sequencing analysis of washed platelets and their releasates after 5 days of AngII infusion revealed significant transcriptomic changes, suggesting rapid reprogramming of platelet function. Parallel RNA-seq analysis of suprarenal aortic tissue highlighted changes in genes associated with extracellular matrix (ECM) organization, inflammation, and platelet signaling, linking platelets to vascular remodeling suggesting a "platelet-aorta axis". Laser speckle imaging in a FeCl₃ injury model confirmed that VAMP8 deficiency impaired platelet function, resulting in delayed thrombosis. In vivo experiments demonstrated that VAMP8⁻/⁻ mice were protected against AngII-induced AAA and aortic rupture. Aortic diameter analysis further revealed that VAMP8 deficiency significantly attenuated AngII-driven aortic pathology. RNA-seq analysis of platelets and aortic tissue suggests that loss of VAMP8 affects expression of genes controlling ECM degradation and aortic wall stability consistent with the protective effect of VAMP8 loss on AAA. CONCLUSION: Short-term AngII infusion appears to reprogram the platelet transcriptome, which may affect the aorta and contribute to AAA formation. Controlling cargo release from platelets via VAMP8 deficiency results in profound attenuation of aortic aneurysms. This introduces a novel paradigm for understanding the impact of reprogrammed platelet cargo secretion and function in aortopathies. HIGHLIGHTS: Platelet transcriptome is altered at early aneurysmal stage.VAMP8 deficiency attenuates aortic aneurysms, potentially via enhanced ECM stability.VAMP8 deficiency significantly alters various genes contributing to aortic wall structure and stability in both platelets and suprarenal aortic tissue.