MIR503HG Loss Promotes Endothelial-to-Mesenchymal Transition in Vascular Disease

João P Monteiro, Julie Rodor, Axelle Caudrillier, Jessica P Scanlon, Ana-Mishel Spiroski, Tatiana Dudnakova, Beatrice Pflüger-Müller, Alena Shmakova, Alex von Kriegsheim, Lin Deng, Richard S Taylor, John R Wilson-Kanamori, Shiau-Haln Chen, Kevin Stewart, Adrian Thomson, Tijana Mitić, John D McClure, Jean Iyinikkel, Patrick Wf Hadoke, Laura DenbyAngela C Bradshaw, Paola Caruso, Nicholas W Morrell, Jason C Kovacic, Igor Ulitsky, Neil C Henderson, Andrea Caporali, Matthias S Leisegang, Ralf P Brandes, Andrew H Baker

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Endothelial-to-mesenchymal transition (EndMT) is a dynamic biological process involved in pathological vascular remodelling. However, the molecular mechanisms that govern this transition remain largely unknown, including the contribution of long non-coding RNAs (lncRNAs). Objective: To investigate the role of lncRNAs in EndMT and their relevance to vascular remodelling. Methods and Results: To study EndMT in vitro, primary endothelial cells (EC) were treated with transforming growth factor-β2 and interleukin-1β. Single-cell and bulk RNA-sequencing were performed to investigate the transcriptional architecture of EndMT and identify regulated lncRNAs. The functional contribution of seven lncRNAs during EndMT was investigated based on a DsiRNA screening assay. The loss of lncRNA MIR503HG was identified as a common signature across multiple human EC types undergoing EndMT in vitro. MIR503HG depletion induced a spontaneous EndMT phenotype, while its overexpression repressed hallmark EndMT changes, regulating 29% of its transcriptome signature. Importantly, the phenotypic changes induced by MIR503HG were independent of miR-424 and miR-503, which overlap the lncRNA locus. The pathological relevance of MIR503HG down-regulation was confirmed in vivo using Sugen/Hypoxia (SuHx)-induced pulmonary hypertension (PH) in mouse, as well as in human clinical samples, in lung sections and blood outgrowth endothelial cells (BOECs) from pulmonary arterial hypertension (PAH) patients. Overexpression of human MIR503HG in SuHx mice led to reduced mesenchymal marker expression, suggesting MIR503HG therapeutic potential. We also revealed that MIR503HG interacts with the Polypyrimidine Tract Binding Protein 1 (PTB1) and regulates its protein level. PTBP1 regulation of EndMT markers suggests that the role of MIR503HG in EndMT might be mediated in part by PTBP1. Conclusions: This study reports a novel lncRNA transcriptional profile associated with EndMT and reveals the crucial role of the loss of MIR503HG in EndMT and its relevance to pulmonary hypertension.

Original languageEnglish
JournalCirculation Research
Early online date11 Mar 2021
DOIs
Publication statusE-pub ahead of print - 11 Mar 2021

Keywords

  • Endothelium
  • endothelial-to-mesenchymal transition
  • EndMT
  • lncRNA
  • miRNA
  • endothelial cell
  • endothelial cell differentiation
  • vascular remodeling
  • molecular biology
  • non-coding RNA

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