Introduction
Hypertensive disorders of pregnancy such as preeclampsia and gestational
hypertension are associated with a higher risk of cardiovascular disease
for both mother and offspring in later life. Women with these
complications during pregnancy have a 4-fold increased risk of
developing hypertension (Bellamy, Casas,
Hingorani & Williams, 2007; McDonald,
Malinowski, Zhou, Yusuf & Devereaux, 2008) and a 2-fold increased risk
of developing stroke after pregnancy (Bellamy et al., 2007). Offspring
from mothers with hypertensive disorders of pregnancy are also likely to
have a higher risk of hypertension and other cardiovascular disease in
later in life (Ferreira, Peeters &
Stehouwer, 2009; Kajantie, Eriksson,
Osmond, Thornburg & Barker, 2009).
The maternal cardiovascular system must undergo significant remodelling
to support the growing fetus. By term, the uteroplacental bed receives
more than 12% of cardiac output. In order to accommodate this increase
in flow, vascular resistance is reduced by outward remodeling and
vasodilatation of more proximal uterine arteries, together with
trophoblast invasion and remodelling of spiral arteries
(Kelly, Stone & Poston, 2000). Failure
of this vascular adaptation is associated with adverse outcomes
including pregnancy induced hypertension and pre-eclampsia. Therefore,
understanding the mechanisms underlying vascular adaptations and how
they impact blood pressure regulations during pregnancy are of great
importance.
Nitric oxide (NO), generated by endothelial nitric oxide synthase
(eNOS), is a key mediator of vascular adaptation in pregnancy. During
pregnancy, enhanced uteroplacental vasodilation is driven by increased
NOS-derived NO in humans, mice, and rats
(Anumba, Robson, Boys & Ford, 1999;
Miller, Jenkin & Walker, 1999;
Sladek, Magness & Conrad, 1997;
Williams, Vallance, Neild, Spencer &
Imms, 1997). Increased uterine artery calibre is associated with both
enhanced eNOS expression, activity, and NO bioavailability
(Cooke & Davidge, 2003;
Nelson, Steinsland, Wang, Yallampalli,
Dong & Sanchez, 2000; Sullivan, Grummer,
Yi & Bird, 2006) (Dimmeler, Fleming,
Fisslthaler, Hermann, Busse & Zeiher, 1999;
Kublickiene, Cockell, Nisell & Poston,
1997). Loss of eNOS leads to impaired uterine artery remodelling during
pregnancy mediated in part by a reduced activation of matrix
metalloproteinase in eNOS- knockout mice
(van der Heijden, Essers, Fazzi, Peeters,
De Mey & van Eys, 2005). NO bioavailability is also central to
physiological adaptation in the more distal uteroplacental circulation
with increased expression of eNOS observed in remodelling spiral
arteries and in cytotrophoblasts and syncytiotrophoblasts
(Lyall, Bulmer, Kelly, Duffie & Robson,
1999). However, simple strategies attempting to restore or augment NO
with NO donors in pre-eclampsia have been disappointing
(Meher & Duley, 2007). One possible
explanation for these results is the failure to specifically target eNOS
uncoupling and consequently altered NO/ROS signalling. To date, there is
less certainty regarding the role of eNOS coupling and NO
bioavailability in the uterine circulation in pregnancy induced
hypertension and pre-eclampsia.
The generation of NO by eNOS requires the small molecule
tetrahydrobiopterin (BH4). Loss of BH4 results in eNOS uncoupling, loss
of NO generation and increased production of reactive oxygen species
(ROS). Biosynthesis of BH4 is catalyzed by GTPCH (GTP cyclohydrolase 1,
encoded by Gch1 , the rate-limiting enzyme for de novo BH4
biosynthesis. We have previously shown that Gch1 expression is a
key determinant of BH4 bioavailability, NOS regulation and NO and
superoxide generation (Crabtree et al.,
2009; Vasquez-Vivar, Martasek, Whitsett,
Joseph & Kalyanaraman, 2002). Recently, we have demonstrated that
maternal endothelial cell BH4 deficiency, due to loss of Gch1 ,
leads to progressive hypertension and fetal growth restriction during
pregnancy (Chuaiphichai et al., 2021).
However, the mechanism mediating these changes and how loss of
endothelial cell-specific Gch1 alters uterine artery function
both before and during pregnancy and if these changes are reversable are
yet to be answered. To address this question, we assessed vascular
function and blood pressure in pregnant and non-pregnant endothelial
cell specific Gch1 knock out mice.