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

Pediatric Research (2026)Cite this article

Abstract

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.

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Fig. 1
Fig. 2: Umbilical cord oxygenation status.
Fig. 3: Expression of HIF1A, ADRB3, and VEGFA mRNA across gestation.
Fig. 4: Correlation between HIF1A, ADRB3, and VEGFA mRNA expression.
Fig. 5: Protein expression of HIF-1α, β3-AR, and VEGF in a small subset of neonates.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We sincerely thank Jean-Luc Baroni and Cristina Ranzato for their exceptional support throughout this study.

Funding

Specifically, we would like to indicate that these analyses were supported by funds from the Italian Ministry of Universities and Research (Progetto di Ricerca di Rilevante Interesse Nazionale – PRIN), project entitled “OBERON – Oxygen dependence of the functional role of Beta3 adRenoceptors: nOvel iNsights from animal models of human neonatal diseases” (grant number 2022FYBMEX).

Author information

Author notes

  1. These authors contributed equally: Alessandro Pini, Luca Filippi.

Authors and Affiliations

  1. Neonatology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Rosa Teresa Scaramuzzo, Lucrezia Filippini & Luca Filippi

  2. Department of Pediatric Hematology-Oncology, A. Meyer Children’s Hospital IRCCS, Florence, Italy

    Maura Calvani, Bianca Tirinnanzi & Stefania Crucitta

  3. Department of Faculty Medicine, Saint Camillus International University of Health and Medical Sciences, Rome, Italy

    Marzia Del Re

  4. Section of Statistics, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Riccardo Morganti

  5. Department of Biology, Unit of General Physiology, University of Pisa, Pisa, Italy

    Lorenza Di Marsico, Maurizio Cammalleri, Paola Bagnoli & Massimo Dal Monte

  6. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    Alessandro Pini

  7. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Luca Filippi

Authors
  1. Rosa Teresa Scaramuzzo
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  2. Lucrezia Filippini
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Contributions

R.T.S.: Interpretation of data, revision of the manuscript, and final approval. Lucr.F.: Acquisition of biological samples and interpretation of data, revision, and final approval. M.Cal.: Analysis, interpretation, and description of genetic results, revision of manuscript, and final approval. B.T.: Analysis, interpretation, and description of genetic results, revision of manuscript, and final approval. S.C.: Analysis, interpretation, and description of genetic results, revision of manuscript and final approval. M.D.R.: Analysis, interpretation, and description of genetic results, revision of manuscript and final approval. R.M.: statistical analysis, revision of manuscript and final approval. L.D.M.: Analysis, interpretation of results. M.Cam.: Interpretation of results, revision of manuscript. P.B.: Interpretation of results, revision of manuscript. M.D.M.: Interpretation of results, revision of manuscript. A.P.: Analysis of biological samples and interpretation of data, review of manuscript. Luca F.: Conception and design, acquisition of clinical and biological data, analysis and interpretation of data and results, writing primary draft of manuscript, revision, and final approval. Luca F. wrote the first draft of the manuscript.

Corresponding author

Correspondence to Luca Filippi.

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Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its subsequent amendments. The research protocol was approved by the Pediatric Ethics Committee for Clinical Research of the Tuscany Region, Italy (approval number 318/2021).

Consent statement

Consent was obtained from the parents according to the research protocol approved by the Pediatric Ethics Committee for Clinical Research of the Tuscany Region, Italy (approval number 318/2021).

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Scaramuzzo, R.T., Filippini, L., Calvani, M. et al. HIF1A, ADRB3, and VEGFA gene expression in human cord blood across gestation: insights toward a pharmacological artificial placenta. Pediatr Res (2026). https://doi.org/10.1038/s41390-026-04879-8

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