von Willebrand Factor Deficiency Inhibits Endothelial-to-Mesenchymal Transition to Attenuate Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, interstitial lung disease lacking an efficient drug to reverse it. Thus, there is an urgent need to elucidate the complex pathogenesis of IPF and identify new therapeutic targets. It has been revealed that the pathophysiology of IPF is a highly orchestrated process that includes multiple cell types in which the contribution of endothelial cells (ECs) has attracted researchers' attention. However, although the involvement of ECs in fibrosis has been recognized, the underlying key molecules driving these changes are not well defined. In this study, we revealed that von Willebrand factor (VWF), a marker of damaged ECs, and endothelial dysfunction are positively correlated with IPF progression on the basis of reanalysis of gene expression profiles of patients with IPF. Next, we discovered that VWF deficiency attenuated fibrosis in experimental models, including human cell lines (in vitro) and mice (in vivo). Mechanistically, VWF deficiency inhibited endothelial-to-mesenchymal transition, regulated vascular abnormalities, and limited M2 macrophage infiltration, which were achieved, at least in part, by the inhibition of Wnt signaling. Our findings provided evidence for the pivotal role of ECs in IPF and revealed that VWF might be a driving factor of endothelial-to-mesenchymal transition, suggesting that VWF can be developed as a potential therapeutic target against IPF.