Signals from the extracellular matrix: Region- and sex-specificity in cardiac aging

Figure 1. ECM alterations in aging heart tissue at different length scales. Tissue organization changes with age due to cardiomyocyte hypertrophy, fibroblast activation, macrophage infiltration, and ECM remodeling (left panel). Zooming into the ECM (middle panel), aging results in structural and compositional changes (e.g., increased collagen V and VI, fibronectin), including at the fibril level (e.g., accumulation of advanced glycation end-products, AGEs, on collagen and glutathionylation of fibronectin fibers – right panel). Changes in ECM are accompanied by integrin activation and clustering that initiate mechanosignaling pathways. ECM: Extracellular matrix; Col: Collagen.

Figure 2. ECM-driven cellular signaling in cardiac aging. Specific age-related ECM alterations activate distinct downstream signaling pathways in cardiomyocytes (top left panel), fibroblasts (bottom panel), and macrophages (top right panel) leading to tissue remodeling and fibrosis. In cardiomyocytes, young ECM maintains homeostasis through basal level integrin receptor activation and signaling, thereby preserving actin cytoskeletal dynamics and sarcomeric contracility. In contrast, aged ECM – characterized by increased stiffness stemming from accumulation of advanced glycation end-products (AGEs), excessive ECM deposition/abundance, and altered topography – activates the FAK/Src axis and Piezo1 pathways, resulting in impaired contractility, reduced Cx43, and hypertrophy. In macrophages, recruitment to fibrotic regions contributes to ECM remodeling. Glycoprotein non-metastatic melanoma protein B (GPNMB) is secreted, which binds to the ECM and transduces signals to cardiomyocytes and fibroblasts, inducing hypertrophy and ECM production, respectively. Macrophages also sense fragmented matrix through integrins, initiating cardiac repair processes. In fibroblasts, aged ECM promotes…