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@ARTICLE{Laban:292100,
      author       = {H. Laban and S. Siegmund and K. Schlereth and F. A.
                      Trogisch and A. Ablieh and L. Brandenburg and A. Weigert and
                      C. De La Torre and C. Mogler and M. Hecker and W. M. Kuebler
                      and T. Korff},
      title        = {{N}uclear factor of activated {T}-cells 5 is indispensable
                      for a balanced adaptive transcriptional response of lung
                      endothelial cells to hypoxia.},
      journal      = {Cardiovascular research},
      volume       = {120},
      number       = {13},
      issn         = {0008-6363},
      address      = {Oxford},
      publisher    = {Oxford University Press},
      reportid     = {DKFZ-2024-01599},
      pages        = {1590-1606},
      year         = {2024},
      note         = {2024 Nov 5;120(13):1590-1606 / (DKFZ-ZMBH Alliance)},
      abstract     = {Chronic hypoxia causes detrimental structural alterations
                      in the lung, which may cause pulmonary hypertension and are
                      partially mediated by the endothelium. While its relevance
                      for the development of hypoxia-associated lung diseases is
                      well known, determinants controlling the initial adaptation
                      of the lung endothelium to hypoxia remain largely
                      unexplored.We revealed that hypoxia activates the
                      transcription factor nuclear factor of activated T-cells 5
                      (NFAT5) and studied its regulatory function in murine lung
                      endothelial cells (MLECs). EC-specific knockout of Nfat5
                      (Nfat5(EC)-/-) in mice exposed to normobaric hypoxia $(10\%$
                      O2) for 21 days promoted vascular fibrosis and aggravated
                      the increase in pulmonary right ventricular systolic
                      pressure as well as right ventricular dysfunction as
                      compared with control mice. Microarray- and single-cell
                      RNA-sequencing-based analyses revealed an impaired growth
                      factor-, energy-, and protein-metabolism-associated gene
                      expression in Nfat5-deficient MLEC after exposure to hypoxia
                      for 7 days. Specifically, loss of NFAT5 boosted the
                      expression and release of platelet-derived growth factor B
                      (Pdgfb)-a hypoxia-inducible factor 1 alpha
                      (HIF1α)-regulated driver of vascular smooth muscle cell
                      (VSMC) growth-in capillary MLEC of hypoxia-exposed
                      Nfat5(EC)-/- mice, which was accompanied by intensified VSMC
                      coverage of distal pulmonary arteries.Collectively, our
                      study shows that early and transient subpopulation-specific
                      responses of MLEC to hypoxia may determine the degree of
                      organ dysfunction in later stages. In this context, NFAT5
                      acts as a protective transcription factor required to
                      rapidly adjust the endothelial transcriptome to cope with
                      hypoxia. Specifically, NFAT5 restricts HIF1α-mediated Pdgfb
                      expression and consequently limits muscularization and
                      resistance of the pulmonary vasculature.},
      keywords     = {Endothelial cells (Other) / Hypoxia (Other) / NFAT5 (Other)
                      / Pulmonary hypertension (Other) / Transcriptome (Other)},
      cin          = {A190},
      ddc          = {610},
      cid          = {I:(DE-He78)A190-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39107245},
      doi          = {10.1093/cvr/cvae151},
      url          = {https://inrepo02.dkfz.de/record/292100},
}