The reason is that BH4 is not only a co-factor of PAH in the liver, but is also involved in cerebral neurotransmission by its co-factor and/or chaperone activities for Tyr hydroxylase (TH), tryptophan hydroxylase (TPH), and nitric oxide synthase [6,7,8] (Supplementary Figure S1B,C). This evidence concerns the gene TH and pulmonary arterial hypertension.