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Pulmonary fibrosis is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix components. Although the origin of fibroblasts is multifactorial, recent data implicate endothelial-to-mesenchymal transition as an important source of fibroblasts. We report herein that loss of the essential autophagy gene ATG7 in endothelial cells (ECs) leads to impaired autophagic flux accompanied by marked changes in EC architecture, loss of endothelial, and gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition. Loss of ATG7 also up-regulates TGFβ signaling and key pro-fibrotic genes in vitro. In vivo , EC-specific ATG7 knock-out mice exhibit a basal reduction in endothelial-specific markers and demonstrate an increased susceptibility to bleomycin-induced pulmonary fibrosis and collagen accumulation. Our findings help define the role of endothelial autophagy as a potential therapeutic target to limit organ fibrosis, a condition for which presently there are no effective available treatments. Background: Endothelial-to-mesenchymal transition (EndMT) is implicated in the development of organ fibrosis. Results: Loss of the autophagy gene ATG7 promotes EndMT and up-regulates TGFβ signaling and the associated pro-fibrotic genes. Endothelial-specific ATG7 knock-out mice exhibited increased bleomycin-induced pulmonary fibrosis. Conclusion: ATG7 is a novel regulator of EndMT-induced organ fibrosis. Significance: Intact endothelial autophagy prevents aberrant EndMT and represents a potential target to limit organ fibrosis.
Singh et al. (Sat,) studied this question.