Several interrelated mechanisms support the idea that MTHFR-mediated disruption in the folate cycle may trigger endothelial dysfunction: Under methylic surcharge and methionine deficiency, L-Arg may be directly converted to ADMA [29], a powerful endogenous inhibitor of eNOS; moreover, homocysteine-dependent downregulation of dimethylarginine dimethyl-aminohydrolase (DDAH) results in increased ADMA levels and endothelial dysfunction [30,31], as observed in patients exposed to methionine loading tests [32]. This evidence concerns the gene MTHFR and endothelial dysfunction.