The causative role of BH4 depletion in endothelial dysfunction can be demonstrated by restored endothelium-dependent dilation with overexpression of the BH4 rate-limiting enzyme, guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) in apolipoprotein E knockout (ApoE KO) mice [40]. This evidence concerns the gene APOE and endothelial dysfunction.