Background: Endothelial dysfunction is a hallmarks of heart failure with preserved ejection fraction (HFpEF). The mechanism by which endothelial oxygen sensing influences cardiomyocyte metabolism and diastolic function remains unknown. Objective: To determine the role of endothelial prolyl hydroxylase domain protein 2 (PHD2), a key oxygen sensor that regulates endothelial homeostasis, in regulating cardiac mitochondrial metabolism and function. Methods and Results: We generated endothelial-specific PHD2 knockout (PHD2ECKO) mice to investigate the impact of endothelial oxygen sensing on cardiac metabolism and function. Male PHD2f/f and PHD2ECKO mice at 8-10 months old were studied. PHD2ECKO hearts exhibited impaired mitochondrial Ca 2+ uptake, reduced pyruvate dehydrogenase (PDH) activity, diminished fatty acid oxidation, and decreased aconitase and succinate-supported respiration, while pyruvate- and α-ketoglutarate–driven respiration and membrane potential were preserved. Complex I respiration and reactive oxygen species (ROS) generation were increased, together with compensatory elevation of complex IV activity. Western blotting revealed downregulation of SERCA2, GLUT4, mitochondrial pyruvate carrier, HADHA, and HADHB. Endothelial cells from PHD2ECKO mice showed reduced eNOS phosphorylation and elevated arginase activity, consistent with impaired endothelial NO signaling. Echocardiography revealed a dilated heart with declined diastolic function, shown as an impaired E’/A’ ratio in PHD2ECKO mice, suggesting developed diastolic dysfunction with preserved systolic function. Conclusions: Endothelial PHD2 couples oxygen sensing to NO signaling and cardiomyocyte mitochondrial Ca 2+ uptake, thereby maintaining metabolic flexibility and diastolic function. Loss of endothelial PHD2 drives metabolic remodeling, oxidative stress, and diastolic dysfunction, revealing a novel mechanism of endothelium-to-myocyte metabolic communication relevant to HFpEF pathogenesis. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Brown et al. (Fri,) studied this question.