Fellowship for Shayan Mohammadmoradi: Role of Platelet-Drive VAMP8 in Abdominal Aortic Aneurysm

Project Summary The role of platelets as vascular sentries in abdominal aortic aneurysm (AAA) development remains underexplored, despite their critical function in maintaining vascular homeostasis. AAA, characterized by aortic dilation and aortic wall remodeling, is often linked to increased platelet activation, leading to intraluminal thrombus (ILT) formation and an elevated risk of rupture. While antiplatelet therapies have been considered for AAA treatment, their efficacy has been inconsistent due to a limited mechanistic understanding, particularly regarding the contribution of platelet granule cargo release. Many platelet functions in homeostasis are mediated by the exocytosis of granule contents, yet this aspect of platelet biology in AAA has received little attention. Previous work from our laboratory has identified Vesicle-Associated Membrane Protein 8 (VAMP8) as the critical regulator of platelet granule secretion. My data demonstrate that VAMP8 deficiency significantly reduces AAA formation in an angiotensin II (AngII)-infused mouse model, suggesting that platelet exocytosis plays a potential role in AAA progression. I also observed increased platelet and VAMP8 abundance in aneurysmal tissue, along with significant transcriptomic alterations in genes related to extracellular matrix organization and inflammation in isolated platelets during the pre-aneurysmal stage. This proposal aims to expand on these findings by addressing the central hypothesis that VAMP8-driven platelet granule secretion contributes to the onset of AAA. In first aim, I will characterize the platelet phenotype in AngII-induced AAA using a battery of platelet-specific functional assays and assess proteomic alterations in the platelet releasate. In second aim, I will examine the progression of AngII-induced AAA in a platelet-specific VAMP8-/- mice, with aortic phenotype and histological analyses performed at study termination, comparing the findings to those from global VAMP8-/- mice. Given the high mortality rates associated with aortic aneurysms and dissections, this research could provide critical translational insights into novel preventive and therapeutic strategies, aligning with the AHA’s mission. In addition to offering a valuable training opportunity that builds on my previous experience while introducing new techniques and areas of expertise, this project aims to deliver a comprehensive understanding of the role of platelets and their granule cargo in the development of AAA.