Cytochrome P450 reductase (POR) shares structural features, substrate, redox cofactors and ancestors with eNOS (endothelial nitric oxide synthase) and Nox (NADPH oxidases), the most studied enzymes in vascular redox homeostasis. POR provides the electrons for cytochrome P450 enzymes which metabolize xenobiotics and endogenous lipids. Importantly, the cardiovascular relevance of POR is largely unknown. To identify its function in the vascular system, we generated an endothelial-specific, tamoxifen-inducible POR knockout mice (ecPOR^-/-). In an in vivo AngII model, acute deletion of POR increased the blood pressure as measured by telemetry and tail cuff (137.4 ± 15.9 mmHg in WT; 152.1 ± 7.154 mmHg in ecPOR^-/-). Most strikingly, already under basal condition ecPOR^-/- exhibit endothelial dysfunction [relaxation to acetylcholine: EC50: 2.4*10-8 M (WT) and 6.2*10-8 M (ecPOR^-/-)], lower nitric oxide production (detected as nitrite in plasma), and heart and cardiomyocyte hypertrophy (heart to body weight and cardiomyocyte area, respectively). Importantly, also cardiac ejection fraction was decreased by endothelial-specific POR deletion (echocardiogram). MACE-RNAseq from the mouse aorta revealed a significant increase in genes annotated to electron transport chain and thermogenesis (Cox8b, Cox7a1) and hypertrophic cardiomyopathy (lamin and tropomyosin) in ecPOR^-/-. Collectively, the signature suggests that endothelial cells support adjacent cells with fatty acids which are the major energetic source of cardiomyocytes. In the absence of POR this endothelial function is compromised leading to negative cardiac metabolic remodeling.