Abstract 139: Contribution Of Platelet Granule Cargo Uptake And Secretion To The Initiation And Progression Of Aortic Aneurysms

Aortic aneurysms present as aortic widening and often catastrophic rupture. While precipitated by a thrombo-inflammatory environment, underlying pathological mechanisms are unclear and adequate treatment is lacking. Antithrombotics have been implied as therapy, but few studies have defined how platelets contribute to aortic aneurysms. We studied the role of platelet granule cargo uptake and secretion in aortic aneurysm formation. Aneurysms were induced in mice defective in platelet α-granule biogenesis (Nbeal2 -/- , Serglycin -/- ), endocytosis (Arf6 -/- , VAMP2/3 Δ ), and exocytosis (Munc13-4 Jinx ) via: i.p. injection of an AAV vector with a mouse PCSK9 gain-of-function mutation; western diet; and continuous s.c. infusion of angiotensin II. Thoracic and abdominal aneurysm formation was assessed with ultrasound. At 4 and 12 weeks, or after rupture, aortas were harvested, analyzed, and prepared for histology. During the study, 30% (3/10) of Nbeal2 -/- and 21.4% (3/18) of Munc13-4 Jinx mice suffered aortic rupture, compared to 0% (0/26) of wildtype mice. In the survivors, the inner diameter of neither the thoracic nor abdominal aorta of Nbeal2 -/- mice changed over time. Ex vivo , Serglycin -/- mice showed a clear, more distributed, widening of the thoracic and descending aorta instead of local aneurysm formation with an increased maximum outer diameter of the ascending region. Munc13-4 Jinx mice had an all-or-nothing phenotype; either early-stage massive aneurysm formation or rupture, or a more diffused phenotype. Mice with platelet endocytosis defects survived and at early stages, the differential increase in the inner diameter of both the thoracic and abdominal aorta was higher in female Arf6 -/- mice. Similarly, VAMP2/3 Δ mice had the largest inner thoracic diameter increase after 28 days. Arf6 -/- and VAMP2/3 Δ mice showed a smaller maximum outer diameter of the descending aorta as wildtype. Preliminary histology shows reduced elastin breaks in all genetic strains, especially in Nbeal2 -/- and VAMP2/3 Δ mice. Our data show that platelet granule cargo exerts significant but perhaps contrasting effects on aortic aneurysm formation. By comparing phenotypes, more detailed mechanistic insights into the role of platelets in aortic aneurysms are possible.