miR-205-5p drives endothelial dysfunction and senescence in pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a fatal, aging-related disease characterized by persistent lung fibroblast activation, progressive lung scarring and several vascular abnormalities. We have previously demonstrated that aging-associated vascular dysfunction drives maladaptive endothelial responses to injury and exacerbates lung fibrosis via secretion of pro-fibrotic endothelial-derived factors. However, regulatory mechanisms governing endothelial dysfunction during progressive lung fibrosis remain poorly understood. Here, using preclinical mouse models of progressive lung fibrosis as well as human IPF lungs, we demonstrate that miR-205-5p is overexpressed in lung ECs from fibrotic lungs, and coordinates gene expression programs implicated in endothelial dysfunction and progressive fibrosis. Transcriptomic profiling revealed that miR-205-5p downregulates genes involved in cell cycle progression while upregulating multiple genes encoding secreted mediators of fibrosis and components of the senescence-associated secretory phenotype, that recapitulating the aberrations observed in lung ECs isolated from human IPF lungs. In addition, miR-205-5p induces the expression of the senescence marker β-galactosidase in lung ECs, mirroring the phenotype of IPF lung ECs, which are also β-galactosidase positive. Consistently, conditioned medium derived from lung ECs overexpressing miR-205-5p promotes lung fibroblast activation. Importantly, miR-205-5p inhibition in IPF lung ECs reduced the transcription of genes encoding soluble mediators of fibroblast activation, confirming the role of miR-205-5p in driving pathogenic endothelial phenotypes during IPF. Collectively, our findings support a novel connection between lung endothelial miR-205-5p and pro-fibrotic alteration of the endothelial secretome, highlighting miR-205-5p as potential therapeutic target in pulmonary fibrosis.