In contrast, the inducible Gch1fl/flVE-Cad-Cre model, in which BH4 is depleted acutely in adulthood, these protective mechanisms fail to provide adaptation, particularly in male mice, resulting in marked eNOS uncoupling, reduced NO bioavailability, impaired vasodilation, and progressive hypertension. Here, NOS3 is linked to hypertensive disorder.