Abstract 279: Intricate Roles Of Myeloid-derived Thrombospondin-1 In Aortic Aneurysm And Rupture

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Introduction: Abdominal aortic aneurysm (AAA) is the progressive weakening and dilation of the aorta. Aneurysm rupture is the major cause of mortality among AAA patients, but its molecular mechanism is still unclear. We previously reported elevated expression of thrombospondin-1 (TSP1), a matricellular protein, in human and mouse AAA. We also identified Mφs as the major source of TSP1. In this study, we investigated the role of myeloid-derived TSP1 in AAA and rupture. Methods and Results: Male myeloid-specific TSP1 deficient mice ( Thbs1 Δ Mφ ) and wildtype littermates ( Thbs1 wt ) were challenged with angiotensin II (Ang II) coupled with hypercholesterolemia. Sixty-one percent of Thbs1 Δ Mφ died from AAA rupture, an incidence that was 2.6 times higher than Thbs1 wt (n=23 for Thbs1 wt , n=30 for Thbs1 Δ Mφ ). Intriguingly, Thbs1 Δ Mφ that survived to the end of 28-day Ang II infusion had less aortic dilation than Thbs1 wt . Majority of the rupture occurred between 7 to 14 days of Ang II infusion. Ultrasound imaging at early time points (baseline, 3 or 7 days after AAA induction) showed no difference in the aortic diameters between genotypes. To understand the molecular mechanisms underlying the rupture-prone phenotype of Thbs1 Δ Mφ , we conducted single-cell RNA sequencing on the aortic tissues 7 days after AAA induction. Thbs1 Δ Mφ showed increased percentages of smooth muscle cells (SMCs), and decreased Mφs and fibroblasts. Six functional SMC subclusters were identified, which were contractile, fibroblast-like, proliferative, macrophage-like, hemoglobin positive, and intermediate SMCs. Thbs1 Δ Mφ specifically increased the intermediate SMCs, all the other subclusters were decreased. Pathway analysis revealed an extended reduction of extracellular matrix-related genes. Histological analysis confirmed the predicted matrix weakening caused by the myeloid-specific TSP1 deficiency. Conclusions: Myeloid TSP1 is critical for Mφ infiltration, which fuels aneurysm growth. However, Mφs, likely through signaling to SMCs and fibroblasts via TSP1, may also contribute to the vascular remodeling at least in the Ang II-induced aortopathy. Therefore, Thbs1 Δ Mφ provides a unique model to investigate the complex interplays between Mφs and vascular cells in AAA and rupture.