The major findings of this study are (1) loss of endothelial cell BH4 is sufficient to increase the sensitivity to Ang II–mediated hemodynamic responses; (2) Ang II infusion exacerbates eNOS uncoupling, increasing aortic eNOS-derived H2O2 production in Gch1fl/flTie2cre mice; (3) endothelial cell-specific Gch1 deficiency causes medial hypertrophy and dysfunction in resistance arteries in response to chronic Ang II infusion; and (4) chronic Ang II infusion leads to pathological vascular remodeling with a greatly increased incidence of AAA in Gch1fl/flTie2cre mice. Here, GCH1 is linked to triple-A syndrome.