High altitude regulates the expression of AMPK pathways in human placenta

Introduction: High-altitude (>2500 m) residence augments the risk of intrauterine growth restriction (IUGR) and preeclampsia likely due, in part, to uteroplacental hypoperfusion. Previous genomic and transcriptomic studies in humans and functional studies in mice and humans suggest a role for AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR. AMPK is a metabolic sensor activated by hypoxia that is ubiquitously expressed in vascular beds and placenta. Methods: We measured gene expression and protein levels of AMPK and its upstream regulators and downstream targets in human placentas from high (>2500 m) vs. moderate (similar to 1700 m) and low (similar to 100 m) altitude. Results: We found that phosphorylated AMPK protein levels and its downstream target TSC2 were increased in placentas from high and moderate vs. low altitude, whereas the phosphorylated form of the downstream target translation repressor protein 4E-BP1 was increased in high compared to moderate as well as low altitude placentas. Mean birth weights progressively fell with increasing altitude but no infants, by study design, were clinically growth-restricted. Gene expression analysis showed moderate increases in PRKAG2, encoding the AMPK gamma 2 subunit, and mechanistic target of rapamycin, MTOR, expression. Discussion: These results highlight a differential regulation of placental AMPK pathway activation in women residing at low, moderate or high altitude during pregnancy, suggesting AMPK may be serving as a metabolic regulator for integrating hypoxic stimuli with placental function.

Automated summary

The study found differential regulation of placental AMPK pathway activation in women residing at low, moderate, or high altitude during pregnancy, suggesting AMPK may serve as a metabolic regulator for integrating hypoxic stimuli with placental function. AMPK and its downstream targets were found to be upregulated in high and moderate altitude placentas, with varying levels of expression observed in different altitude groups. Despite decreasing birth weights with increasing altitude, no infants were clinically growth-restricted in this study.