Hypoxia-driven crosstalk among cardiac fibroblasts, macrophages, and endothelial cells in cardiac fibrosis
TL;DR
This mini-review presents the latest evidence on hypoxia-driven fibrosis through three processes: fibroblast activation and myofibroblast differentiation, macrophage polarization and paracrine effects, and endothelial-to-mesenchymal transition (EndMT).
Abstract
Cardiac fibrosis, a hallmark of adverse remodeling following myocardial infarction (MI), markedly contributes to progressive heart failure. Severe tissue hypoxia within the ischemic heart activates hypoxia-inducible factor (HIF) signaling, thereby reshaping intercellular communication among non-myocytes. This mini-review presents the latest evidence on hypoxia-driven fibrosis through three processes: (i) fibroblast activation and myofibroblast differentiation, (ii) macrophage polarization and paracrine effects, and (iii) endothelial-to-mesenchymal transition (EndMT). Recent single-cell transcriptomics studies have revealed fibroblast/immune cell heterogeneity post-injury, while metabolic shifts (e.g., glycolytic reprogramming, lactate-histone lactylation, and glutamine persistence) link hypoxia to the epigenetic regulation of fibrosis. Novel therapies, including lactate-scavenging biomaterials, eNAMPT neutralization, and timed metalloproteinase inhibition, show promise in targeting these pathways. A deeper understanding of hypoxia-mediated crosstalk may lead to the development of strategies to mitigate maladaptive fibrosis while preserving reparative scarring following MI.