Inducible Endothelial Gch1 Deletion Reveals Rapid, Sex-Specific Effects on Blood Pressure and Pregnancy Outcomes.

Abstract

BACKGROUND Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase. Constitutive endothelial BH4 deficiency leads to mild hypertension and vascular dysfunction that are partly compensated by alternative endothelium-derived vasodilators. Accordingly, we generated a novel VE-Cadherin-CreERT2 (VE-Cad-Cre) mouse to evaluate the impact of inducing endothelial-specific BH4 deficiency in adult animals, without the potential mitigating effects of developmental or other adaptive mechanisms. METHODS Endothelial Gch1 deletion and BH4 deficiency were induced by tamoxifen administration to Gch1fl/flVE-Cad-Cre male and female adult mice. In female mice, endothelial BH4 deficiency was also induced immediately before pregnancy. The effects of inducible Gch1 deletion were determined on BH4 levels, vascular function, blood pressure, and fetal development during pregnancy. RESULTS Male and female Gch1fl/flVE-Cad-Cre mice had normal blood pressure. However, tamoxifen treatment of male Gch1fl/flVE-Cad-Cre mice caused progressive hypertension with impaired nitric oxide synthase-mediated vasodilation. Tamoxifen treatment of female Gch1fl/flVE-Cad-Cre mice led to nonprogressive hypertension that was exacerbated by pregnancy, leading to impaired uteroplacental vascular function and fetal growth restriction. CONCLUSIONS Induction of endothelial cell BH4 deficiency reveals rapid, sex-specific requirements for endothelial cell BH4 in vascular function and blood pressure, and the cardiovascular response to pregnancy. These changes are more striking than those reported for constitutive endothelial cell BH4 deficiency, suggesting a role for developmental or other adaptive effects that fail to mitigate the effects of inducible endothelial cell BH4 deficiency. Targeting endothelial BH4 bioavailability may offer therapeutic strategies for acquired hypertensive disorders and fetal growth restriction.