High‐elevation adaptation and gestational hypoxia jointly shape vascular development in a rodent placenta

Gestational hypoxia reduces fetal growth and birth weight across mammals, including humans. Evolutionary adaptation to high-elevation hypoxia mitigates these negative effects, and identifying these protective mechanisms may offer insight into how environmental factors interact with gestational physiology to influence health outcomes. We know that gestational hypoxia modifies development of the placenta, which mediates maternal-fetal exchange, but little is known about how high-altitude adaptation interacts with this developmental plasticity to influence placental exchange capacity. We tested the hypothesis that hypoxia-dependent remodelling of the placental exchange surface is protective for fetal growth and thus will be exaggerated in highland-adapted individuals by using a model rodent system, the North American deer mouse. We acclimated lowland- and highland-ancestry deer mice to normoxia or hypoxia (12.3% O₂) during gestation and found that lowland-ancestry deer mice expand their placenta and maternal blood spaces in the placenta in response to environmental hypoxia. Highland-ancestry deer mice produce even larger placentas and maternal blood spaces, suggesting that these hypoxia-driven responses may benefit fetal growth by increasing total exchange capacity. Notably, we also found that the fetal blood spaces in highland-ancestry placentas have increased perimeter (a proxy for surface area) per unit area occupied by blood. Similar changes to fetal vasculature have been observed in high-elevation-adapted human populations, which is suggestive of convergent adaptation. Our results demonstrate that the hypoxia-sensitive development of placental vasculature is remodelled by adaptation to environmental hypoxia and that some of these processes may be points for convergent adaptation across species despite distinct placental architectures. KEY POINTS: Evolutionary adaptation to high elevations provides protection against hypoxia-dependent fetal growth restriction. The placenta is a key determinant of fetal growth because it defines the total surface area available for nutrient and gas exchange between the gestational parent and offspring. We tested the hypothesis that evolutionary adaptation to high elevations protects fetal growth by increasing placental surface area for exchange using acclimation experiments in a model rodent system, the North American deer mouse. As we predicted, high-elevation ancestry increased the size of maternal blood spaces in the placenta, especially under gestational hypoxia; however, highland ancestry was also associated with narrower fetal blood spaces, which could increase exchange efficiency. The patterns observed in deer mice resemble developmental plasticity observed in placentas from humans with high-elevation ancestry, pointing to potential for convergent adaptation across species with distinct placental architectures.