β3‐Adrenoceptor Agonism to Mimic the Biological Effects of Intrauterine Hypoxia: Taking Great Strides Toward a Pharmacological Artificial Placenta

At different stages of life, from embryonic to postnatal, varying oxygen concentrations modulate cellular gene expression by enhancing or repressing hypoxia-inducible transcription factors. During embryonic/fetal life, these genes encode proteins involved in adapting to a low-oxygen environment, including the induction of specific enzymes related to glycolytic metabolism, erythropoiesis, angiogenesis, and vasculogenesis. However, oxygen concentrations fluctuate during intrauterine life, enabling the induction of tissue-specific differentiation processes. Fetal well-being is thus closely linked to the physiological benefits of a dynamically hypoxic environment. Premature birth entails the precocious exposure of the immature fetus to a more oxygen-rich environment compared to the womb. As a result, preterm newborns face a condition of relative hyperoxia, which alters the postnatal development of organs and contributes to prematurity-related diseases. However, until recently, the molecular mechanism by which high oxygen tension alters normal fetal differentiation remained unclear. In this review, we discuss the research trajectory followed by our research group, which suggests that early exposure to a relatively hyperoxic environment may impair preterm neonates due to reduced expression of the β3-adrenoceptor. Additionally, we explore how these impairments could be prevented through the pharmacological stimulation of the remaining β3-adrenoceptors. Recent preclinical studies demonstrate that pharmacological stimulation of the β3-adrenoceptor can decouple exposure to hyperoxia from its harmful effects, offering a glimpse of the possibility to recreating the conditions typical of intrauterine life, even after premature birth.