Abstract 208: The Chromatin Remodeling Protein Brg1 Regulates Adventitial Progenitor Cell Myofibroblast Differentiation And Pathological Vascular Remodeling

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 42; no. Suppl_1; p. A208
• Main Authors: Jolly, Austin, Lu, Sizhao, Dubner, Allison, Mutryn, Marie, Navarro, Natalie, Nemenoff, Raphael, Weiser-Evans, Mary C
• Format: Journal Article
• Language: English
• Published: Lippincott Williams & Wilkins 01.05.2022
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/atvb.42.suppl_1.208

Cardiovascular diseases lead to long-term stiffening of arteries and small vessels. The vascular wall contains several cellular populations that coordinate to maintain vessel homeostasis and induce vascular remodeling in disease states. We identified a population of smooth muscle-derived progenitor cells that reside in the adventitial layer (AdvSca1-SM cells) that drive vascular fibrosis after acute vascular injury. AdvSca1-SM cells can differentiate into myofibroblasts and secrete numerous pro-remodeling factors including extracellular matrix proteins and pro-inflammatory cytokines. While the response of AdvSca1-SM cells to vascular injury has been studied, the epigenetic changes that influence their differentiation towards myofibroblasts is poorly understood. We observed Brahma-related gene 1 (Brg1), a highly conserved chromatin remodeling ATPase, is upregulated in AdvSca1-SM cells in response to vascular injury and may be a key factor in regulating gene expression to influence AdvSca1-SM differentiation. We hypothesize that Brg1 induces expression of gene sets associated with remodeling and fibrosis and ultimately drives AdvSca1-SM cell differentiation towards pathologic myofibroblasts. ResultsCarotid arteries from mice subject to carotid ligation exhibit decreased perivascular collagen deposition, smaller neointima, decreased adventitial expansion, decreased numbers of alpha-actin positive AdvSca1-SM cells, and fewer infiltrating macrophages when treated with the pharmacological Brg1 bromodomain inhibitor PFI-3 as compared to mice that received vehicle control. In a cell culture system, TGF-β induces AdvSca1-SM cells to express myofibroblast-specific genes, including alpha actin and periostin, and demonstrate enhanced contractile function in collagen contraction assays. PFI-3 blocks TGF-β induced myofibroblast gene expression and dampens contractile function. Gene Ontology analysis reveals the top 100 TGF-β inducible genes blunted by PFI-3 are related to fibrosis and extracellular matrix signaling. In conclusion, these results suggest Brg1 is a major regulator of vascular remodeling and fibrosis and may be a targetable protein to help people who suffer from disease-related vascular stiffening.