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bioRxiv · 10.1101/2025.10.14.682369

Loss of miRNA-153 promotes endothelial-to-mesenchymal transition and compromises lung vascular integrity

Elmadbouh, I.·Zhong, Z.·Wang, L.·Thompson, M.·Hoeppner, L.·Prakash, Y. S.·Yuan, J.·Pabelick, C.·Babicheva, A.
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Abstract

Endothelial-to-mesenchymal transition (EndMT) is a biological process through which lung vascular endothelial cells (ECs) transdifferentiate into mesenchymal-like cells. EndMT has recently been implicated in the development and progression of pulmonary vascular remodeling in pulmonary hypertension (PH); however, its underlying regulatory mechanisms remain incompletely understood. MicroRNAs (miRNAs) are key post-transcriptional regulators of EC gene expression and cellular responses to various stimuli. Notably, microRNA-153 (miR-153) has been shown to directly target SNAI1 to modulate epithelial-to-mesenchymal transition (EMT), a process closely related to EndMT and extensively studied in cancer. Whether miR-153 also participates in EndMT regulation, however, remains unknown. In this study, we demonstrate that 72-hour hypoxic exposure induces SNAI1-mediated EndMT in human lung vascular ECs. Hypoxia also increased cell proliferation and disrupted intercellular junctions, leading to enhanced endothelial permeability. Reduced miR-153 expression was observed in both hypoxia- and TGF-{beta}1-induced EndMT, as well as in ECs isolated from PH patients exhibiting an EndMT phenotype. Similar to hypoxia, TGF-{beta}1 promoted EC permeability. Loss of miR-153 enhanced SNAI1-mediated EndMT, endothelial survival, and permeability under normoxic conditions, whereas miR-153 overexpression attenuated EndMT induced by hypoxia or TGF-{beta}1. However, miR-153 restoration did not completely recover endothelial barrier integrity disrupted by these stimuli. In conclusion, miR-153 serves as a critical regulator of EndMT, maintaining endothelial identity and barrier function. Therapeutic delivery of miR-153 may therefore represent a novel strategy to inhibit EndMT and attenuate pulmonary vascular remodeling in PH.

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Elmadbouh, I., Zhong, Z., Wang, L., Thompson, M., Hoeppner, L., Prakash, Y. S., Yuan, J., Pabelick, C., Babicheva, A.. 2025-10-15. Loss of miRNA-153 promotes endothelial-to-mesenchymal transition and compromises lung vascular integrity. https://doi.org/10.1101/2025.10.14.682369

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