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| Item Type: | Preprint |
|---|---|
| Title: | Endothelial YAP/TAZ rewiring under cardiometabolic stress drives sex-divergent vascular remodeling in heart failure with preserved ejection fraction |
| Creators Name: | Klaus-Bergmann, Alexandra, Sievers, Laura Katharina, Versnjak, Jakob, Koch, Katharina, Nawara, Tomasz, Bartels-Klein, Eireen, Popp, Oliver, Weiner 3rd, January, Meier, Katja, Hollfinger, Irene, Kamer, Ilona, Taube, Martin, Heuser, Arnd, Borodina, Tatiana, Beule, Dieter, Potente, Michael, Landmesser, Ulf, Mertins, Philipp, Kelm, Marcus, Muller, Dominik N. and Gerhardt, Holger |
| Abstract: | Heart failure with preserved ejection fraction (HFpEF) is widely linked to endothelial dysfunction, yet the molecular pathways translating cardiometabolic stress into microvascular remodeling remain poorly defined. Here, we identify endothelial YAP/TAZ signaling as a mechanistic regulator of sex-divergent vascular responses in HFpEF. Plasma proteomics from the UK Biobank revealed elevated circulating YAP1 levels associated with heart failure and increased mortality, particularly in male patients, where YAP1 coincided with increased levels of the endothelial activation marker ESM1. In a hypertensive cardiorenal mouse model, endothelial YAP/TAZ deletion preserved cardiac function, whereas endothelial TAZ gain-of function aggravated disease. Under cardiometabolic stress (TNFα and high glucose), endothelial cells exhibited sex-specific rewiring of YAP/TAZ-dependent transcriptional programs. Male endothelial cells showed increased extracellular YAP1 release, angiogenic instability with impaired extracellular matrix remodeling, whereas female cells adopted an immune-primed, stress-adaptive phenotype. Mechanistically, cardiometabolic stress uncoupled canonical YAP-TEAD transcription and engaged alternative cofactors, including VGLL3 and VGLL4, thereby reshaping the endothelial secretome and propagating sex divergent microvascular remodeling. These findings identify endothelial YAP/TAZ rewiring as a molecular switch that converts cardiometabolic stress into sex-divergent microvascular remodeling in HFpEF and connect this process to circulating YAP1 and ESM1 in patients. |
| Keywords: | Heart Failure, Endothelial Dysfunction, Mechanobiology, Vascular Remodelling, Plasma Proteomics, Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.05.07.723127 |
| Date: | 13 May 2026 |
| Additional Information: | Accession "GSE320481" is currently private and is scheduled to be released on Jan 31, 2027. |
| Official Publication: | https://doi.org/10.64898/2026.05.07.723127 |
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