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Mitomycin C induces pulmonary vascular endothelial‐to‐mesenchymal transition and pulmonary veno‐occlusive disease via Smad3‐dependent pathway in rats
Author(s) -
Zhang Chenting,
Lu Wenju,
Luo Xiaoyun,
Liu Shiyun,
Li Yi,
Zheng Qiuyu,
Liu Wenyan,
Wu Xuefen,
Chen Yuqin,
Jiang Qian,
Zhang Zizhou,
Gu Guoping,
Chen Jiyuan,
Chen Haixia,
Liao Jing,
Liu Chunli,
Hong Cheng,
Tang Haiyang,
Sun Dejun,
Yang Kai,
Wang Jian
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15314
Subject(s) - mesenchymal stem cell , cd31 , vimentin , medicine , endothelium , pathology , endothelial dysfunction , immunohistochemistry
Background and Purpose Pulmonary veno‐occlusive disease (PVOD) is a rare disease characterized by the obstruction of small pulmonary veins leading to pulmonary hypertension. However, the mechanisms underlying pulmonary vessel occlusion remain largely unclear. Experimental Approach A mitomycin C (MMC)‐induced PVOD rat model was used as in vivo animal model, and primarily cultured rat pulmonary microvascular endothelial cells (PMVECs) were used as in vitro cell model. Key Results Our data suggested an endothelial‐to‐mesenchymal transition (EndoMT) may be present in the pulmonary microvessels isolated from either PVOD patients or MMC‐induced PVOD rats. In comparison to the control vessels, vessels from both PVOD patients and PVOD rats had co‐localized staining of specific endothelial marker von Willebrand factor (vWF) and mesenchymal marker α‐smooth muscle actin (α‐SMA), suggesting the presence of cells that co‐express endothelial and mesenchymal markers. In both the lung tissues of MMC‐induced PVOD rats and MMC‐treated rat PMVECs there were decreased levels of endothelial markers (e.g. VE‐cadherin and CD31) and increased mesenchymal markers (e.g. vimentin, fibronectin and α‐SMA) were detected indicating EndoMT. Moreover, MMC‐induced activation of the TGFβ/Smad3/Snail axis, while blocking this pathway with either selective Smad3 inhibitor (SIS3) or small interfering RNA (siRNA) against Smad3, dramatically abolished the MMC‐induced EndoMT. Notably, treatment with SIS3 remarkably prevented the pathogenesis of MMC‐induced PVOD in rats. Conclusions and Implications Our data indicated that targeted inhibition of Smad3 leads to a potential, novel strategy for PVOD therapy, likely by inhibiting the EndoMT in pulmonary microvasculature.