Hypoxia-driven crosstalk among cardiac fibroblasts, macrophages, and endothelial cells in cardiac fibrosis

FIGURE 1. Hypoxia-orchestrated intercellular crosstalk network in cardiac fibrosis. The central hypoxic microenvironment (blue) activates HIF-1α/HIF-2α signaling, a process that can be therapeutically enhanced by roxadustat to promote the polarization of reparative macrophages. The solid black arrows indicate direct paracrine activation. Macrophage-derived oncostatin M (OSM), TGF-β1, and IL-11 promote fibroblast-to-myofibroblast differentiation, while MT1-MMP-mediated TGF-β1 activation induces EndMT. Fibroblast-derived lactate promotes EndMT through Snail1 lactylation via MCT1-dependent signaling. Left panel (Metabolism): YAP-driven glycolytic shifts and the PFKFB3/OTUD4 axis promote metabolic reprogramming, leading to histone lactylation and glutamine catabolism, which subsequently disrupt fibroblast lineage fidelity. Right panel (Epigenetic): Multilayered epigenetic regulatory mechanisms, including m6A modification, circular RNAs, and DNA methylation, promote the profibrotic phenotype. Top panel (Cellular Heterogeneity): Key cell populations identified by single-cell RNA sequencing (scRNA-seq), including CTHRC1+/POSTN + fibroblasts and FAP+/POSTN + matrifibrocytes. Also shown is the…

FIGURE 2. Temporal dynamics of hypoxia-driven cardiac remodeling post-myocardial infarction (MI). The wound-healing cascade following MI progresses through three distinct phases: inflammation (days 0–3), proliferation (days 3–7), and maturation (weeks 2–4+), with persistent tissue remodeling during the chronic stages. Top: Spatial gradient from the infarct core to the remote myocardium. Three major cell populations undergo coordinated transitions: Fibroblasts progress from quiescent to activated states (characterized by upregulation of hypoxia-inducible factor (HIF)-1α and PFKFB3) before transitioning to Postn+/CTHRC1+ myofibroblasts and ultimately FAP+/POSTN + matrifibrocytes, which are involved in extracellular matrix (ECM) crosslinking. Macrophages transition from Ly6Chi inflammatory (M1-like) to Ly6Clo reparative (M2-like) phenotypes, producing OSM, IL-11, and TGF-β1 while directly depositing collagen. Endothelial cells undergo partial endothelial-to-mesenchymal transition (EndMT) via Snail1/Twist activation and lactate-mediated Snail1 lactylation. Bottom: ECM accumulation trajectory with therapeutic windows (green, beneficial timing; red, detrimental timing for ADAM17 inhibition).