Endothelial GTPCH (GTP Cyclohydrolase 1) and Tetrahydrobiopterin Regulate Gestational Blood Pressure, Uteroplacental Remodeling, and Fetal Growth.

Surawee Chuaiphichai,Gillian Douglas,Yasmin Dickinson,Eileen Mcneill,Mahesh Appari,Nicholas J Alp,Paul Leeson,Wei Zhang,Ashley B Hale,Edward N Drydale,Christopher Whiteman,Manu Vatish,Mark J Crabtree,Keith M Channon,Grace Z Yu,Cheryl M.J Tan,Adam J Lewandowski

doi:10.1161/hypertensionaha.120.17646

Abstract

[Figure: see text].

Highlights

Abnormal uteroplacental remodeling leads to placental hypoperfusion, causing fetal growth restriction and pregnancy-related hypertension, which are associated with endothelial dysfunction and markers of reduced vascular NO bioavailability and oxidative stress
Using multiple complementary in vitro, ex vivo, and in vivo translational models, we demonstrate that deficiency in endothelial cell BH4 biosynthesis contributes to pregnancy-induced hypertension and intrauterine growth restriction
These findings suggest a novel role of endothelial cell BH4 biosynthesis in vascular adaptations and blood pressure regulation during pregnancy

Summary

Introduction

Abnormal uteroplacental remodeling leads to placental hypoperfusion, causing fetal growth restriction and pregnancy-related hypertension, which are associated with endothelial dysfunction and markers of reduced vascular NO bioavailability and oxidative stress. Using mice models and human samples, we investigated the physiological requirement for endothelial cell BH4 in uteroplacental vascular adaptation and blood pressure regulation to pregnancy. Selective maternal endothelial BH4 deficiency resulting from targeted deletion of Gch[1] caused progressive hypertension during pregnancy and fetal growth restriction. We demonstrate that a selective change in endothelial function is sufficient to cause pregnancy-related hypertension, deficient uteroplacental vascular remodeling, and reduced fetal growth, using a targeted mouse model of endothelial cell deficiency of tetrahydrobiopterin. We demonstrate that supplementation of tetrahydrobiopterin (BH4) with the fully reduced folate, 5-methyltetrahydrofolate, could restore BH4 levels, and correct the pregnancy phenotype in Gch1fl/flTie2cre mice, whereas supplementation with BH4 alone was ineffective

Methods

Results

Discussion

Conclusion