Contribution of smooth muscle-derived vascular progenitor cells to atherosclerosis
| Autor: | Allison Dubner, Sizhao Lu, Austin Jolly, Tysen Noble, Karen Moulton, Raphael Nemenoff, Mary Weiser-Evans |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Physiology. 38 |
| ISSN: | 1548-9221 1548-9213 |
| DOI: | 10.1152/physiol.2023.38.s1.5733626 |
| Popis: | Purpose: Atherosclerosis is a major cause of morbidity and mortality worldwide, but current therapies fail to adequately meet clinical needs. Emerging evidence implicates the outer layer of the blood vessel, the adventitia, in the pathogenesis of atherosclerosis. Specifically, it has been suggested that expansion of adventitial microvessels, the vasa vasorum (VV), drives atherosclerosis by facilitating inflammatory cell infiltration. Our group previously identified a unique population of multipotent resident vascular stem cells (AdvSca1-SM cells) that derive from mature vascular smooth muscle cells (SMCs) and reside in the vessel adventitia, where they are poised to respond to vascular injury. The goal of this project was to determine the contribution of AdvSca1-SM cells to the chronic vascular injury response. We hypothesized that in the setting of atherosclerosis, AdvSca1-SM cells contribute to plaque growth or VV expansion to drive disease progression. Methods: We generated a highly specific lineage tracing mouse model to track AdvSca1-SM cells in vivo over time. Lineage tracing mice were placed on either normal chow or modified Western diet (combined with PCSK9 AAV) for 8 to 30 weeks, then vascular tissue was analyzed using IF microscopy, scRNA-Seq, 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, but these cells showed significant phenotypic shifts compared to control conditions. Additionally, genetic modulation of the AdvSca1-SM cells influenced the transcriptional profiles of non-AdvSca1-SM-derived cells, indicating a signaling role for AdvSca1-SM cells in the vascular microenvironment. When AdvSca1-SM cells differentiate into other cell types, they primarily become mature SMCs, modulated SMCs, and myofibroblasts. These AdvSca1-SM-derived SMCs and myofibroblasts can be found in the core of the plaque, the fibrous cap, and the media wall. Additionally, these cells can be associated with adventitial microvessels in plaque regions, suggesting a role in plaque neovascularization. Contrary to our preliminary data, AdvSca1-SM cells very rarely differentiate into endothelial cells or macrophages. Conclusions: These studies emphasize the dynamic nature of AdvSca1-SM cells in the vascular injury response, demonstrating the potential of these cells to both differentiate into a variety of cell types as well as signal to other cells in the vascular wall. Ongoing studies will further characterize the distinct contributions of AdvSca1-SM cells to atherosclerosis. NHLBI F31 (Dubner, HL160149-01); NHLBI R01 (Weiser-Evans, HL121877) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process. |
| Databáze: | OpenAIRE |
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