AMPK function in uterine vasculature and placenta at high altitude

The chronic hypoxia of high-altitude (HA, >2500 m) residence reduces uterine artery (UtA) blood flow, contributing to an increased frequency of fetal growth restriction (FGR). FGR pregnancies have reduced UtA blood flow partially owing to impaired myometrial artery (MyoA) vasodilation. However, studies show lower rates of HA-associated reductions in fetal growth in Andeans and describe an association between genetic variants predicted to activate the AMP-activated protein kinase (AMPK) pathway and protection against low birthweight. Vascular function studies show that AMPK-dependent vasodilator responses are amplified in UtA from mice exposed to hypoxia during pregnancy and MyoA from pregnant women at HA, while the response is reduced in MyoA from women with FGR pregnancies. The effect of HA (or gestational hypoxia) on placental AMPK activation needs to be clarified, with some studies showing an effect and others not. There is potential to use AMPK activators as therapeutic targets. However, some drugs (i.e. metformin) approved for use in pregnancy complications cause off-target and adverse metabolic effects in offspring, which discourage their use. Future studies are warranted to elucidate the mechanisms underlying the altitude-dependent activation of AMPK in uncomplicated pregnancies and its reduction in FGR to identify possible vascular-specific targets for therapeutic intervention. This article is part of the discussion meeting issue ‘Pregnancy at high altitude: the challenge of hypoxia’.