Endothelial cells as regulatory hubs in the fibrotic microenvironment.

Tissue fibrosis is a common pathological response to chronic injury and a major contributor to progressive organ dysfunction. In the lung, liver, heart, kidney, skin, and other organs, persistent inflammation, ischemia, toxic injury, metabolic stress, or immune dysregulation can shift repair from adaptive remodeling toward scar formation. Once extracellular matrix (ECM) deposition becomes self-sustaining, current therapies often slow progression but rarely reverse established fibrosis. Increasing attention has therefore shifted from individual effector cells to the profibrotic microenvironment in which parenchymal cells, stromal cells, immune cells, vascular cells, soluble mediators, and the ECM interact. Within this environment, vascular endothelial cells are no longer viewed only as passive vascular barriers. They can sense hypoxia, inflammatory mediators, oxidative stress, altered shear stress, and matrix stiffness, and they may contribute to barrier remodeling, immune-cell recruitment, angiocrine signaling, metabolic adaptation, and endothelial phenotype plasticity. In this review, we synthesize current evidence on endothelial involvement in fibrotic microenvironments across organs. We use the term "regulatory hubs" to describe the anatomical and functional position of endothelial cells as signal-integrating cells within tissue niches, not to imply that they universally initiate or control fibrosis. Particular attention is given to endothelial heterogeneity, single-cell and spatial transcriptomic findings, organ-specific endothelial states, and therapeutic implications. Throughout the manuscript, observational omics data are interpreted as evidence of association, spatial organization, or candidate communication unless supported by functional perturbation, lineage tracing, or rescue experiments.