NFAT5-dependent transcriptional stress control of endothelial cells prevents maladaptive remodeling of pulmonary arterioles in the hypoxic lung
bioRxiv (Cold Spring Harbor Laboratory)(2023)
摘要
Aims Chronic hypoxia causes detrimental structural alterations in the lung, which are partially dependent on stress responses of the endothelium. In this context, we revealed that hypoxia-exposed murine lung endothelial cells (MLEC) activate nuclear factor of activated T-cells 5 (NFAT5) - a transcription factor that adjusts the cellular transcriptome to cope with multiple environmental stressors. Here, we studied the functional relevance of NFAT5 for the control of hypoxia-induced transcription in MLEC.
Methods and Results Targeted ablation of Nfat5 in endothelial cells did not evoke phenotypic abnormalities in normoxia-exposed mice. However, MLEC in Nfat5 -deficient mice up-regulated energy- and protein-metabolism-associated gene expression under normobaric hypoxia (10% O2) for seven days as evidenced by microarray- and scRNA-seq-based analyses. Moreover, loss of NFAT5 boosted the expression and release of platelet-derived growth factor B ( Pdgfb) - a HIF1α-regulated driver of vascular smooth muscle cell (VSMC) growth - in capillary MLEC of hypoxia-exposed mice, which was accompanied by exaggerated coverage of distal pulmonary arterioles by VSMC, increased pulmonary vascular resistance and impaired right ventricular functions. In vitro, knockout of Nfat5 in cultured MLEC stimulated Pdgfb expression and release after exposure to hypoxia and amplified binding of HIF1α in the Pdgfb promoter region.
Conclusion Collectively, our study identifies NFAT5 as a protective transcription factor required to rapidly adjust the transcriptome of MLEC to hypoxia. Specifically, NFAT5 restricts HIF1α-mediated Pdgfb expression and consequently limits muscularization and resistance of pulmonary arterioles.
Highlights
![Figure][1]
### Competing Interest Statement
The authors have declared no competing interest.
[1]: pending:yes
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关键词
endothelial cells,pulmonary arterioles,lung
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