A Vascular Microphysiological Model of Lung Fibrosis Reveals That Myofibroblasts and IPF Patient‐Derived Fibroblasts Impair Angiogenesis and Vasculogenesis

ABSTRACT Lung fibrosis, characterized by chronic and progressive scarring, has no cure. Its hallmarks are the accumulation of myofibroblasts and extracellular matrix, as well as vascular remodeling. The crosstalk between myofibroblasts and vasculature is poorly understood, with conflicting reports on whether angiogenesis and vessel density are increased or decreased in lung fibrosis. Here, we develop a microphysiological system that recapitulates the pathophysiology of lung fibrosis and disentangles myofibroblast‐vascular interactions. In this model, lung myofibroblasts induced by TGF‐β1 treatment maintain their phenotype in 3D without exogenous TGF‐β1 and display anti‐angiogenic and anti‐vasculogenic activities when cultured with endothelial cells in a microfluidic device. Similar effects, including decreased endothelial sprouting and increased vascular permeability, are observed with fibroblasts derived from idiopathic pulmonary fibrosis patients. Pharmacological interventions with the TGF‐β receptor type I inhibitor SB‐431542 and VEGF supplementation restore vascular morphology and permeability, demonstrating the responsiveness of the model. This system provides insights into myofibroblast‐vascular crosstalk in lung fibrosis and offers a platform to evaluate therapies targeting vascular integrity.