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Heart failure with preserved ejection fraction (HFpEF) is linked to co-morbidity induced systemic inflammation causing endothelial dysfunction and perturbed endothelial-myocardial signaling leading to functional and structural alteration in myocardium. Hallmarks of endothelial dysfunction in HFpEF are decreased endothelial nitric oxide synthase (eNOS) and increased reactive oxygen species (ROS) and TGFb production, finally leading to myofibrosis of left ventricular wall and impaired elasticity of the neighboring vessels. In our project, we aim to address the function of endothelial YAP/TAZ (YT) signaling, menchanotranscducers shown to respond to a variety of signals and to target the level of TGFb/BMP output under challenging hemodynamic conditions in the development of HFpEF. We combine mouse, zebrafish, and iPSC models in combination with ex vivo microfluidics to assess inflammatory, physical, and metabolic stress in endothelial cells (EC) and examine endothelial cardiomyocyte signaling and potential pharmacological intervention.
Graphical Abstract: In A03 different experimental models, zebrafish, mouse and patient-derived iPSCs, will be employed to identify how mechanical and metabolic stressors disturb the endothelial YT signaling network dynamics that drive endothelial inflammation, endothelial-myocardial and extracardial pathophysiology of HFpEF. Multi-omics approaches will be used to compare the different models and unravel the molecular mechanism linking metabolism and mechanotransduction of endothelial dysfunction.
Ong YT, Andrade J, Armbruster M, Shi C, Castro M, Costa ASH, Sugino T, Eelen G, Zimmermann B, Wilhelm K, Lim J, Watanabe S, Guenther S, Schneider A, Zanconato F, Kaulich M, Pan D, Braun T, Gerhardt H, Efeyan A, Carmeliet P, Piccolo S, Grosso AR, Potente M. A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth. Nat Metab. 2022 Jun;4(6):672-682. doi: 10.1038/s42255-022-00584-y. Epub 2022 Jun 20. PMID: 35726026; PMCID: PMC9236904.