Abstract 1000: Platelets Act As Circulating Reservoir Of Tgfβ1: Role In Abdominal Aortic Aneurysms

Abstract

Introduction: Transforming Growth Factor-Beta1 (TGFβ1) signaling plays a crucial role in the development and maintenance of the vasculature by orchestrating vascular remodeling signaling cascades. Aberrant TGFβ1 leads to aortic aneurysms, yet there is a persistent conflict in its role in driving or protecting against the degradation of the extracellular matrix (ECM) in abdominal aortic aneurysms (AAA). Notably, limited studies have delved into its cell-specific actions. This ambiguity highlights the need for an improved understanding of the TGFβ1 cell-specific role in AAA. Aims: To elucidate the role of platelet-derived TGFβ1 in AAA development thereon expanding our knowledge on the role of TGFβ1 in vascular remodeling. Methods and Results: Single-cell epitope and transcriptome analysis by using cellular-indexing of transcriptomes and epitopes by sequencing (CITE-seq) of the blood of patients with AAA revealed that platelets were enriched with TGFβ1 compared to healthy individuals. Comparative pathway analysis of the platelet populations showed the association of this cluster with ROS, platelet activation and chemokine signaling pathways that promote AAA pathogenesis. These results were validated in the Apolipoprotein E deficient (ApoE -/- ) mice treated with Angiotensin II for 28 days. To delve into the direct role of platelet-derived TGFβ1 in AAA, we generated mice with conditional knock-down of TGFβ1 in platelets (Tgfb1 flox/flox Pf4 Cre+ ) and subjected these mice to AAA. Remarkably, these mice exhibited reduced aneurysm development and preserved elastin microstructure compared to controls. The expression of phosphorylated smad2/3, one of the downstream TGFβ1-canonical signaling pathways, as well as matrix metalloproteinase, were repressed in the aorta of Tgfb1 flox/flox Pf4 Cre+ mice, suggesting the platelets could supplement Tgfb1 to the aortic tissue sufficient to fuel matrix degradation. These results were recapitulated when the platelets were depleted from the circulation using an anti-GP1b antibody. Conclusion: Our findings reveal that platelets represent an important reservoir of Tgfb1, clarify its cell-specific role in ECM remodeling and underscore its detrimental role in sustaining matrix degradation during AAA.