Hypoxia induces endothelial‑mesenchymal transition in pulmonary vascular remodeling

Zhang,Bo; Niu,Wen; Dong,Hai‑Ying; Liu,Man‑Ling; Luo,Ying; Li,Zhi‑Chao

doi:10.3892/ijmm.2018.3584

Hypoxia induces endothelial‑mesenchymal transition in pulmonary vascular remodeling

Authors:
- Bo Zhang
- Wen Niu
- Hai‑Ying Dong
- Man‑Ling Liu
- Ying Luo
- Zhi‑Chao Li
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Affiliations: Department of Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: March 22, 2018 https://doi.org/10.3892/ijmm.2018.3584
Pages: 270-278
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It is well established that hypoxia induces epithelial‑mesenchymal transition in vitro and in vivo. However, the role of hypoxia in endothelial‑mesenchymal transition (EndMT), an important process in the pathogenesis of pulmonary hypertension, is not well‑characterized. The present study demonstrated a significant downregulation of the endothelial marker CD31 and its co‑localization with a mesenchymal marker, α‑smooth muscle actin (α‑SMA), in the intimal layer of small pulmonary arteries of rats exposed to chronic hypoxia. These results suggest a possible role of hypoxia in inducing EndMT in vivo. Consistent with these observations, pulmonary microvascular endothelial cells (PMVECs) cultured under hypoxic conditions exhibited a significant decrease in CD31 expression, alongside a marked increase in the expression of α‑SMA and two other mesenchymal markers, collagen (Col) 1A1 and Col3A1. In addition, hypoxia promoted the proliferation and migration of α‑SMA‑expressing mesenchymal‑like cells, but not of PMVECs. Of note, knockdown of hypoxia‑inducible factor 1α (HIF‑1α) effectively inhibited hypoxic induction of α‑SMA, Col1A1 and the transcription factor Twist1, while rescuing hypoxic suppression of CD31; these results suggest that HIF‑1α is essential for hypoxia‑induced EndMT and that it serves as an upstream regulator of Twist1. Mechanistically, HIF‑1α was identified to bind to the promoter of the Twist1 gene, thus activating Twist1 transcription and regulating EndMT. Collectively, the present results indicate that the HIF‑1α/Twist1 pathway has a critical role in mediating the effect of hypoxia‑induced EndMT in pulmonary arterial remodeling.

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