Significance The hemochorial placenta is a dynamic structure endowed with responsibilities controlling the extraction of maternal resources, ensuring fetal development and preserving maternal health. A healthy placenta exhibits plasticity and can adapt to environmental challenges. Such adaptations can be executed through instructive actions on trophoblast stem cells, influencing their abilities to expand and differentiate into specialized cells that accommodate the challenge. Hypoxia, when appropriately timed, promotes invasive trophoblast-directed uterine spiral artery remodeling. Hypoxia activates hypoxia inducible factor-dependent expression of lysine demethylase 3A, modifying the histone landscape on key target genes, including matrix metallopeptidase 12, which acts to facilitate trophoblast invasion and uterine vascular remodeling. Plasticity and adaptations at the maternal–fetal interface safeguard placental development and the healthy progression of pregnancy.