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- W4312751019 abstract "Introduction: Loss of vascular smooth-muscle cells (vSMC) and subsequent defective replenishment of functional vSMC de novo are pathological hallmarks of abdominal aortic aneurysm (AAA). Evidence suggests that clusters of progenitors can be reprogrammed into vSMC lineage following vascular injury. However, the landscape of vSMC precursors and reprograming signatures that determine their fate in AAA is undefined. Hypothesis: We hypothesize that quiescent progenitor pools reside in aorta and undergo spatiotemporal fate decision into mature vSMC in AAA. We speculate that distinct ligand-receptor and transcriptional signals gear their pathogenic trajectories into dysfunctional vSMC in AAA. Methods & Results: Single-cell RNA-sequencing (scRNA-seq) identified vascular progenitor cells (Cd34 + Pdgfra + ) in murine (angiotensin II-induced) and human AAA. Pseudotime analysis tracked two differentiation fates of progenitors into divergent mature vSMC pools characterized by enrichment in contractile cytoskeleton machinery (Acta2 + Myh11 + ) or abnormally supplemented with matrix remodeling genes (Mmp2 + Col8a1 + ). Mmp2 + Col8a1 + clusters were dominant in AAA suggesting pathological reprograming in AAA. Gene regulatory network analysis mapped distinct libraries of upstream transcription factors in each mature vSMC states in AAA. Acta2 + Myh11 + and Mmp2 + Col8a1 + transcriptomes were driven by opposing actions of Pparg and its repressor Runx1 respectively. Interestingly, cellular interaction analysis revealed that platelet-derived Pdgfb fueled the phenotypic switch into Mmp2 + Col8a1 + vSMC via its receptor Pdgfra. Dampening Pdgfra signaling by systemic platelet depletion repressed Runx1 activation thereby increasing Pparg transcriptomic activity in progenitors in the aortic wall. This rescued functional regeneration of vSMC (Acta2 + Myh11 + ) with contractile properties consistent with reduced aortic damage and diminished AAA incidence. Conclusion: Our data demonstrate that platelets are novel actors capable of awakening progenitor pools by coding their fate into pathogenic vSMC lineage in AAA. We provide evidence suggesting that strategies aimed at sustaining vSMC contractile destiny could encourage repair of vascular damage in AAA." @default.
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- W4312751019 date "2022-05-01" @default.
- W4312751019 modified "2023-10-09" @default.
- W4312751019 title "Abstract 155: Divergent Mature Vascular Smooth Muscle Cell Fates Are Directed By Platelet-derived Transcriptomic Codes In Aortic Aneurysms." @default.
- W4312751019 doi "https://doi.org/10.1161/atvb.42.suppl_1.155" @default.
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