HIF1A, ADRB3, and VEGFA gene expression in human cord blood across gestation: insights toward a pharmacological artificial placenta

Background: Recent studies have shown that from the 23rd week of gestation onward, the fetus becomes progressively more hypoxic, with oxygenation levels rising again after 33–34 weeks. The biological significance of this biphasic oxygenation pattern has remained unclear. Methods: Umbilical cord blood samples from 100 preterm and 100 full-term neonates were analyzed for blood gas parameters and for HIF1A, ADRB3 (β3-adrenoceptor), and VEGFA gene expression. Results: A progressive increase in mRNA expression of all three genes was observed with advancing gestational age, followed by a decline during the final weeks of pregnancy. This gene expression trend was inversely correlated with fetal oxygenation status. Conclusion: This study demonstrates that β3-adrenoceptor expression progressively increases with gestational age, supporting the concept that this receptor plays a key role in fetal development and well-being. These findings strengthen the evidence from animal models showing that pharmacological activation of β3-adrenoceptors can reproduce, even after birth, some of the beneficial effects normally provided by the intrauterine environment. Collectively, this work supports the conceptual framework for developing a “pharmacological artificial placenta” aimed at mimicking intrauterine conditions to promote physiological neonatal adaptation. Impact: Recent studies have shown that from the 23rd week of gestation onward, the fetus becomes progressively more hypoxic, with oxygenation levels rising again after 33–34 weeks. However, the biological significance of this biphasic oxygenation pattern had remained unclear. This study demonstrates for the first time that fetal oxygen fluctuations are accompanied by a synchronous and coordinated increase in the mRNA expression of HIF1A, ADRB3 (β3-adrenoceptor), and VEGFA genes. These findings support a mechanistic link between intrauterine hypoxia, β3-adrenergic signaling, and fetal maturation. This work contributes to ongoing research suggesting that pharmacological β3-adrenoceptor activation may help recreate intrauterine-like conditions, potentially promoting physiological fetal development in adverse environments.