| Autor: |
Jolly AJ; Department of Medicine, Division of Renal Diseases and Hypertension.; Medical Scientist Training Program., Lu S; Department of Medicine, Division of Renal Diseases and Hypertension.; School of Medicine, Consortium for Fibrosis Research and Translation., Dubner AM; Department of Medicine, Division of Renal Diseases and Hypertension., Strand KA; Department of Medicine, Division of Renal Diseases and Hypertension., Mutryn MF; Department of Medicine, Division of Renal Diseases and Hypertension., Pilotti-Riley A; Department of Medicine, Division of Renal Diseases and Hypertension., Danis EP; Department of Pharmacology., Nemenoff RA; Department of Medicine, Division of Renal Diseases and Hypertension.; School of Medicine, Consortium for Fibrosis Research and Translation.; Cardiovascular Pulmonary Research Program, and., Moulton KS; Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Majesky MW; Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA.; Departments of Pediatrics and Pathology, University of Washington, Seattle, Washington, USA., Weiser-Evans MC; Department of Medicine, Division of Renal Diseases and Hypertension.; School of Medicine, Consortium for Fibrosis Research and Translation.; Cardiovascular Pulmonary Research Program, and. |
| Abstrakt: |
Vascular smooth muscle-derived Sca1+ adventitial progenitor (AdvSca1-SM) cells are tissue-resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and the extracellular matrix. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the AdvSca1-SM-to-myofibroblast transition are unclear. We show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein were upregulated in AdvSca1-SM cells after acute vascular injury, and pharmacological inhibition of Brg1 by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-β1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; PFI blocked TGF-β1-induced phenotypic transition. Similarly, genetic knockdown of Brg1 in vivo reduced adventitial remodeling and fibrosis and reversed AdvSca1-SM-to-myofibroblast transition in vitro. Mechanistically, TGF-β1 promoted redistribution of Brg1 from distal intergenic sites of stemness genes and recruitment to promoter regions of myofibroblast-related genes, which was blocked by PFI-3. These data provide insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating the AdvSca1-SM phenotype will provide antifibrotic clinical benefits. |
