Abstract 452: Contribution Of Smooth Muscle-derived Vascular Progenitor Cells To Atherosclerosis

作者：Allison Dubner, Sizhao Lu, Austin Jolly, Tysen Noble, Raphael A. Nemenoff, Karen S. Moulton, Mary C. Weiser-Evans · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2023 · DOI：10.1161/atvb.43.suppl_1.452 · 研究领域：Angiogenesis and VEGF in Cancer、Cardiovascular Disease and Adiposity、Biomarkers in Disease Mechanisms

Purpose: Atherosclerosis is a major cause of morbidity and mortality worldwide, but current therapies fail to adequately meet clinical needs. Our group discovered a unique population of adventitial multipotent resident vascular stem cells (AdvSca1-SM cells) that derive from mature vascular smooth muscle cells (SMCs) and are poised to respond to vascular injury. The goal of this project was to determine the role of AdvSca1-SM cells in the setting of atherosclerosis. We hypothesized that AdvSca1-SM cells contribute to plaque growth or neovascularization to drive disease progression. Methods: Highly specific AdvSca1-SM cell-specific lineage tracing mice were placed on either normal chow or given PCSK9 AAV injections to induce LDLR KO and placed on a high fat/high cholesterol diet for 8 to 30 weeks. The vasculature was analyzed using scRNA-Seq, immunofluorescence microscopy, and flow cytometry. Results: scRNA-Seq and flow cytometry revealed a large reservoir of AdvSca1-SM cells in a stem-like state in the setting of atherosclerosis, which was expected given the focal nature of plaque formation. However, significant phenotypic shifts in stem-like AdvSca1-SM cells were observed compared to normal chow conditions. Additionally, AdvSca1-SM cell-specific knockout of stemness-associated transcription factor Klf4 altered the phenotype of non-AdvSca1-SM-derived cells, indicating a signaling role for AdvSca1-SM cells to other cells in the vascular microenvironment. We also observed that A...