NFAT5-dependent transcriptional stress control of endothelial cells prevents maladaptive remodeling of pulmonary arterioles in the hypoxic lung

Laban, H.; Siegmund, S.; Schlereth, K.; Brandenburg, L.; Trogisch, F. A.; Weigert, A.; De La Torre, C.; Abukiwan, A.; Mogler, C.; Hecker, M.; Kuebler, W. M.; Korff, T.

doi:10.1101/2023.10.18.563022

bioRxiv · 10.1101/2023.10.18.563022

NFAT5-dependent transcriptional stress control of endothelial cells prevents maladaptive remodeling of pulmonary arterioles in the hypoxic lung

Laban, H.·Siegmund, S.·Schlereth, K.·Brandenburg, L.·Trogisch, F. A.·Weigert, A.·De La Torre, C.·Abukiwan, A.·Mogler, C.·Hecker, M.·Kuebler, W. M.·Korff, T.

View original source ↗Export metadata ↓

Abstract

AimsChronic 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 ResultsTargeted 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 HIF1-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 HIF1 in the Pdgfb promoter region. ConclusionCollectively, our study identifies NFAT5 as a protective transcription factor required to rapidly adjust the transcriptome of MLEC to hypoxia. Specifically, NFAT5 restricts HIF1-mediated Pdgfb expression and consequently limits muscularization and resistance of pulmonary arterioles. HighlightsO_LIHypoxia stimulates the transcriptional activity of NFAT5 in MLEC. C_LIO_LILoss of NFAT5 in hypoxia-exposed MLEC results in EC subtype-specific maladaption of growth factor-, energy- and protein-metabolism-associated gene expression. C_LIO_LISpecifically, NFAT5-deficient capillary lung EC unleash HIF1-regulated Pdgfb expression and release, which results in excessive coverage of pulmonary arterioles by VSMC. C_LIO_LINFAT5-dependent control of early stress responses of capillary MLEC is required to limit the increase in pulmonary vascular resistance and impairment of right ventricular functions. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/563022v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@c9be61org.highwire.dtl.DTLVardef@f1d7cforg.highwire.dtl.DTLVardef@18f795forg.highwire.dtl.DTLVardef@695601_HPS_FORMAT_FIGEXP M_FIG C_FIG

Source connections

Published article ↗

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Laban, H., Siegmund, S., Schlereth, K., Brandenburg, L., Trogisch, F. A., Weigert, A., De La Torre, C., Abukiwan, A., Mogler, C., Hecker, M., Kuebler, W. M., Korff, T.. 2023-10-22. NFAT5-dependent transcriptional stress control of endothelial cells prevents maladaptive remodeling of pulmonary arterioles in the hypoxic lung. https://doi.org/10.1101/2023.10.18.563022

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The canine hair metabolome encodes age and coat exposure in over 700 dogs

Hair can be collected noninvasively and stored for years, making it a practical sample for studying physiology and environmental exposure. Yet the chemical information it carries in dogs remains largely unexplored. We profiled 782 banked hair samples from 700 Golden Retrievers by untargeted liquid chromatography-mass spectrometry, detecting 4,533 compound groups and revealing an unexpectedly rich chemical profile. Prominent signals reflected skin-surface and hair chemistry, including amino acids, peptides and urocanic acid, alongside surfactants, plasticizers and pesticides detectable despite washing. A signal annotated as imidacloprid distinguished dogs receiving topical products containing this insecticide from dogs receiving no flea or tick preventive (AUC 0.865). Hair chemistry also varied with age, most strongly between puppyhood and early adulthood. Oxidized lipids generally declined, whereas amino acids and peptides remained largely stable. A multivariate model estimated age with moderate accuracy (cross-validated r = 0.66) and assigned a higher age to the later sample in 64 of 75 repeatedly sampled dogs. Because age and collection date were strongly correlated, their effects could not be fully separated, although date-restricted analyses supported an age-related contribution. Together, these findings establish banked dog hair as a promising resource for studying chemical exposure and life-stage-associated changes in chemistry.

physiology↗

bioRxiv2026

Dietary Human HSP90 Promotes Longevity and Healthspan in Caenorhabditis elegans via a Multi-Branched Stress Signaling Pathway

The loss of proteostasis is one of the primary drivers of aging. Despite the important role of the molecular chaperone HSP90 in maintaining proteostasis, its systemic role in aging appears contradictory because its inhibitors can effectively extend lifespan across diverse species. This study showed that dietary HSP90 supplementation via Escherichia coli significantly extended lifespan and healthspan of Caenorhabditis elegans without fertility trade-offs. Exogenous HSP90 likely acts as an extracellular signaling ligand that engages downstream kinase networks to drive the activation of three major longevity-associated transcription factors: DAF-16, SKN-1, and HSF-1. In addition, we demonstrated the additive effect of combining dietary HSP90 supplementation with the senolytic HSP90 inhibitor tanespimycin, indicating that extracellular proteostatic signaling and the intracellular inhibition of HSP90 can work together to enhance longevity. Finally, we engineered an antibiotic-free E. coli Nissle 1917 probiotic that constitutively expresses HSP90, which successfully extended the lifespan of C. elegans.

physiology↗

bioRxiv2026

Sex differences in myocardial ketone oxidation capacity in cardiometabolic disease with coincident ischemic heart disease

Background: Myocardial infarction (MI) in patients with heart failure with preserved ejection fraction (HFpEF) is associated with worse outcomes than MI in individuals without HFpEF. However, the molecular mechanisms underlying this increased vulnerability remain poorly understood. We investigated sex differences in cardiac ketone body (KB) metabolism in patients with diabetes-associated ischemic heart disease, and in a mouse model of HFpEF complicated by MI (HFpEF-MI). Methods: Cardiac BDH1 and OXCT1 expression was assessed in male and female patients with diabetes, with or without ischemic heart disease. Male and female mice received a high-fat diet and L-NAME for 10 weeks to induce HFpEF, followed by coronary artery ligation to induce MI. Glucose tolerance, cardiac function, survival, cardiac KB oxidative capacity, and circulating KB levels were evaluated. Results: Cardiac BDH1 and OXCT1 abundance was significantly reduced in male patients with diabetes-associated ischemic heart disease but preserved in female patients. In mice, 10 weeks of high-fat diet and L-NAME administration increased fasting blood glucose and impaired glucose tolerance. MI reduced systolic function in control and HFpEF mice of both sexes. Male HFpEF-MI mice exhibited higher mortality than female HFpEF-MI mice. Consistent with our human results, male HFpEF-MI mice showed reduced cardiac ketolytic enzyme expression alongside elevated circulating KB levels, whereas female mice maintained cardiac KB oxidative capacity. Conclusion: Reduced cardiac ketolytic enzyme expression and impaired KB oxidative capacity are associated with greater mortality in male HFpEF-MI mice, whereas female mice exhibit preserved KB oxidative capacity and improved survival. Similar sex differences in ketolytic enzyme expression were observed in patients with diabetes-associated ischemic heart disease. These findings identify cardiac ketone metabolism as a potential therapeutic target warranting further investigation in HFpEF complicated by MI.

physiology↗