miRNA expression profiling of lung endothelial cells reveals elevated miR-205-5p in aged mice with persistent lung fibrosis and in IPF-derived endothelial cells

Vascular dysfunction contributes to pathological tissue remodeling in aging and Idiopathic Pulmonary Fibrosis (IPF). Using mouse models of lung fibrosis, we have previously showed that young lung endothelial cells (LECs) activate transcriptional programs leading to vascular repair and fibrosis resolution, whereas aged LECs fail to activate these programs, hindering vascular repair and perpetuating fibrosis. miRNAs are small non-coding RNAs involved in gene silencing and post-transcriptional gene regulation. Here, we investigated endothelial miRNA changes associated with resolution in young mouse lungs and disrepair in aged mouse lungs post-bleomycin injury, and their relevance to human disease. We found several miRNAs dysregulated in LECs freshly sorted from the lungs of aged mice with persistent fibrosis compared to young ones, with miR-205-5p and miR-34a-5p emerging as the most upregulated miRNAs. Comparative qPCR analysis of human ECs isolated from healthy and IPF lungs showed increased expression of miR-205-5p in IPF LECs, whereas miR-34a-5p levels were similar in both groups, suggesting a role for endothelial miR-205-5p in mouse and human lung fibrosis. Intriguingly, miRNA-target prediction analysis identified as potential miR-205-5p target genes Pecam1, Aplnr, Foxf1 and Tbx3; these genes are important regulators of endothelial function known to be repressed in IPF LECs. Altogether, our data pave the way for future investigations into the role of miR-205-5p and related pathways in lung vascular responses to injury to identify novel therapeutic approaches for slowing lung fibrosis by manipulating endothelial miRNA.