Abstract Or143: The Transition of Platelets from Sealants to Signalers in Abdominal Aortic Aneurysm Protection via TGFβ1

Background: Abdominal aortic aneurysm (AAA) is a debilitating cardiovascular condition characterized by a localized dilation of the abdominal aorta, leading to a significant risk of rupture. Platelets are not only critical in thrombus formation but serve as vital mediators of inflammatory responses and tissue remodeling. Among the various mediators released by platelets, transforming growth factor beta 1 (TGFβ1) has emerged as a protective agent in AAA pathogenesis. To date, platelets contribution to TGFβ1's protective effects in AAA remains undefined. Methods and Results: We investigated the effects of platelet depletion on AAA progression using multiple mouse models. Platelet depletion was performed with an anti-CD42b antibody (5 µg/g) compared to IgG control (n ≥ 10 all groups, male mice) to evaluate its impact on rupture-induced mortality in hypercholesterolemic Ldlr -/- and apoE -/- mice infused with angiotensin II (AngII, 1,000 ng/kg/min) for 28 days. We also assessed the effects in additional models, including normocholesterolemic C57BL/6J mice, deoxycorticosterone acetate (DOCA)-treated mice, and topical elastase-exposed mice. Platelet depletion significantly increased rupture-induced death in all mouse models, with minimal survivors past day 12 (< 30%), compared to IgG control groups (P < 0.05, all platelet-depleted mice). This effect was not sex-specific, as female C57BL/6J mice in the topical elastase AAA model had >90% ruptured aortas with platelet depletion. All platelet-depleted mice, independent of model, had significantly less circulating plasma TGFβ1 (IgG injected: 91.28 ± 8.29 ng/mL; platelet depleted: 15.82 ± 1.23 ng/mL; P < 0.001). To determine whether platelet depletion-induced reduction of TGFβ1 was responsible for rupture-induced death, male and female Tgfβ1 Flox/Flox Pf4 Cre- and Cre+ mice underwent laparotomy, topical elastase application, and aneurysm growth and analysis for 28 days. Platelet-specific deletion of TGFβ1 augmented aneurysm diameter and rupture in both male and female mice versus Cre- controls (P < 0.05) and also led to the formation of a reproducible intraluminal thrombus. These results were recapitulated when mice were crossed to Ldlr -/- and underwent the AngII aneurysm model (male only). Conclusions: Our research highlights platelets’ crucial role in AAA initiation and progression as essential carriers of TGFβ1. Targeting platelet-mediated TGFβ1 signaling could provide novel therapeutic avenues for managing AAA.