FIGURE 3.

MI fibroblast signaling network. In response to MI, cardiac fibroblasts initially polarize to a proinflammatory phenotype at MI day 1 and secrete cytokines and chemokines (e.g., CXCL1, 2, 5, 8, and 10, CX3C11, CCL2, 3, 5, IL‐1β, IL‐6, IL‐8, IL‐12p40, IL‐12p70, IL‐13, TNFα, Tnfrsf9, and CSF1) to facilitate leukocyte infiltration. By MI day 3, fibroblasts polarize to a more proliferative phenotype (Ckap4 expression) with characteristics of an activated myofibroblast (α‐smooth muscle actin expression and Tgfβ1). Activated myofibroblasts secrete ECM proteins, including collagen I and III, as well as fibronectin that initiates ECM deposition for scar formation. Vascular endothelial growth factor (VEGF) secretion increases at MI day 3, indicating an angiogenic role for fibroblasts. By MI day 7, fibroblasts continue to secrete more ECM proteins (collagen I and III, TIMP‐1, and collagen crosslinking proteins such as SPARC and LOX for scar maturation. Reparative fibroblasts at MI day 7 demonstrate an anti‐angiogenic profile, indicated by expression of thrombospondin 1. Created with Biorender.com