Beyond blood flow: the multifaceted role of AMPK in regulating fetal growth at high altitudes.

Over the past several decades, scientific advancements have propelled efforts towards identifying the mechanisms influencing uteroplacental and fetoplacental perfusion and their role in maintaining sufficient fetal growth. Despite substantial progress, many questions regarding the fundamental biological pathways regulating human fetal growth remain unanswered. High-altitude (HA) studies have long captured the attention of reproductive scientists interested in such questions, given the profound effect of ambient hypoxia on suppressing birth weight and the pregnancy-associated rise in uterine artery (UA) blood flow. However, the lower UA flows cannot be solely responsible for reduced fetal growth at HA, as uterine oxygen supply exceeds placental and fetal oxygen consumption. This suggests that reduced uteroplacental blood flow triggers metabolic responses within the maternal-placental-fetal unit to align fetal growth with oxygen availability. Through the presentation of molecular and physiological studies, this Review proposes that the adenosine monophosphate kinase signalling pathway coordinates uteroplacental perfusion and metabolism in HA pregnancy, regulating fetal growth through its dual roles as a potent vasodilator and a regulator of cellular energy homeostasis. Understanding the mechanisms orchestrating crosstalk between metabolism and perfusion within the maternal-placental-fetal unit at HA will provide deeper insight into the mechanisms by which hypoxia influences fetal growth more generally.This article is part of the discussion meeting issue 'Pregnancy at high altitude: the challenge of hypoxia'.