Endothelial Cell Vasodilator Dysfunction Mediates Progressive
Pregnancy-induced Hypertension in Endothelial Cell Tetrahydrobiopterin
Deficient Mice
Abstract
Background and purpose: Pregnancy-associated vascular remodeling is
essential for both maternal and fetal health. We have previously shown
that maternal endothelial cell tetrahydrobiopterin (BH4) deficiency
causes poor pregnancy outcomes. Here, we investigated the role and
mechanisms of endothelial cell-mediated vasorelaxation function in these
outcomes. Experimental approach: The vascular reactivity of mouse aortas
and uterine arteries from non-pregnant and pregnant endothelial
cell-specific BH4 deficient mice (Gch1fl/flTie2cre mice) was assessed by
wire myography. Systolic blood pressure was assessed by tail cuff
plethysmography. Key results: Key results: In late pregnancy, systolic
blood pressure was significantly higher (~24 mmHg) in
Gch1fl/flTie2cre mice compared with wild-type littermates. This was
accompanied by enhanced vasoconstriction and reduced
endothelial-dependent vasodilation in both aorta and uterine arteries
from pregnant Gch1fl/flTie2cre mice. In uterine arteries loss of
eNOS-derived vasodilators was partially compensated by upregulation of
intermediate and large-conductance Ca2+-activated K+ channels. In rescue
experiments, oral BH4 supplementation alone did not rescue vascular
dysfunction and pregnancy-induced hypertension in pregnant
Gch1fl/flTie2cre mice. However, combination with the fully reduced
folate, 5-methyltetrahydrofolate (5-MTHF), restored endothelial cell
vasodilator function and blood pressure. Conclusions and implications:
We identify a critical requirement for maternal endothelial cell BH4
biosynthesis in endothelial cell vasodilator function in pregnancy.
Targeting vascular Gch1 and BH4 biosynthesis with reduced folates may
provide a novel therapeutic target for the prevention and treatment of
pregnancy-related hypertension.