The cofactor tetrahydrobiopterin (BH₄) is a critical regulator of nitric oxide synthase (NOS) function and redox signaling, with reduced BH₄ implicated in multiple cardiovascular disease states. In the myocardium, augmentation of BH₄ levels can impact on cardiomyocyte function, preventing hypertrophy and heart failure. However, the specific role of endothelial cell BH₄ biosynthesis in the coronary circulation and its role in cardiac function and the response to ischemia has yet to be elucidated. Endothelial cell-specific Gch1 knockout mice were generated by crossing Gch1^fl/fl with Tie2cre mice, generating Gch1^fl/flTie2cre mice and littermate controls. GTP cyclohydrolase protein and BH₄ levels were reduced in heart tissues from Gch1^fl/flTie2cre mice, localized to endothelial cells, with normal cardiomyocyte BH₄. Deficiency in coronary endothelial cell BH₄ led to NOS uncoupling, decreased NO bioactivity, and increased superoxide and hydrogen peroxide productions in the hearts of Gch1^fl/flTie2cre mice. Under physiological conditions, loss of endothelial cell-specific BH₄ led to mild cardiac hypertrophy in Gch1^fl/flTie2cre hearts. Endothelial cell BH₄ loss was also associated with increased neuronal NOS protein, loss of endothelial NOS protein, and increased phospholamban phosphorylation at serine-17 in cardiomyocytes. Loss of cardiac endothelial cell BH₄ led to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia-reperfusion injury. Taken together, these studies reveal a specific role for endothelial cell Gch1/BH₄ biosynthesis in cardiac function and the response to cardiac ischemia-reperfusion injury. Targeting endothelial cell Gch1 and BH₄ biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction and ischemia-reperfusion injury.NEW & NOTEWORTHY We demonstrate a critical role for endothelial cell Gch1/BH₄ biosynthesis in coronary vascular function and cardiac function. Loss of cardiac endothelial cell BH₄ leads to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia/reperfusion injury. Targeting endothelial cell Gch1 and BH₄ biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction, ischemia injury, and heart failure.

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