Supplementation with BH4 fails to prevent vascular
dysfunction and pregnancy-induced hypertension in
Gch1fl/flTie2cre mice, but is rescued by the addition
of reduced folate, 5-Methyltetrahydrofolate.
In our previous study, we showed that treatment of pregnantGch1fl/fl Tie2cre mice with BH4 and 5-MTHF was
sufficient to restoration BH4 levels and prevented fetal growth
restriction and increased blood pressure in late pregnancy
(Chuaiphichai et al., 2021;
Landmesser et al., 2003;
Williams, Vallance, Neild, Spencer &
Imms, 1997). Given the results of our current study we hypothesized
that BH4 and 5-MTHF supplementation is acting to restored blood pressure
and fetal growth via normalization of pregnancy induced vascular
remodelling in Gch1fl/fl Tie2cre mice. To
address this, we treated Gch1fl/fl Tie2cre and
wild-type mice with either oral BH4 or BH4 with 5-MTHF for 3 days prior
to mating, and throughout pregnancy.
We found that oral BH4 supplementation alone was not sufficient to
prevent progressive hypertension throughout pregnancy or restore
vascular function in uterine arteries fromGch1fl/fl Tie2cre mice. With an enhanced
contractile response and reduced sensitivity to the endothelial cell
dependent dilator acetylcholine still observed in pregnantGch1fl/fl Tie2cre mice compared to their wild
type littermates (Figure 5A, B, C and D).
However, the addition of reduced folate, 5-MTHF to BH4 supplementation
resulted in a striking normalization of both the constriction responses
to U46619 and relaxation responses to ACh, inGch1fl/fl Tie2cre mice, restoring the responses
to those observed in wild-type animals. The combination of 5-MTHF to BH4
oral supplementation just prior to conception was sufficient to prevent
progressive pregnancy induced hypertension inGch1fl/fl Tie2cre mice with no difference in
blood pressure observed between wild type andGch1fl/fl Tie2cre mice from 2.5 days
post-conception until the end of the experiment at gestational day 18.5
(Figure 5C and F).