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Downregulation of argininosuccinate synthase 1 (ASS1) is associated with hypoxia in placental development

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Abstract

Argininosuccinate synthase (ASS1) is involved in nitric oxide production, which has a key role in placental development improving pregnancy outcomes. Syncytiotrophoblast and extravillous trophoblast differentiations are milestones of placental development and their impairment can cause pathologies, such as preeclampsia (PE) and fetal growth restriction (FGR). Immunohistochemistry and Western blotting were used to localize and quantify ASS1 in first trimester (8.2 ± 1.8 weeks), third trimester (38.6 ± 1.1 weeks), and PE (36.3 ± 1.5 weeks) placentas. In addition, cell cultures were used to evaluate ASS1 expression under hypoxic conditions and the syncytialization process. Our data showed that ASS1 is localized in the villous cytotrophoblast of first trimester, third trimester, and PE placentas, while the villous cytotrophoblast adjacent to the extravillous trophoblast of cell columns as well as the extravillous trophoblast were negative for ASS1 in first trimester placentas. In addition, ASS1 was decreased in third trimester compared to the first trimester placentas (p = 0.003) and no differences were detected between third trimester and PE placentas. Moreover, ASS1 expression was decreased in hypoxic conditions and syncytialized cells compared to those not syncytialized. In conclusion, we suggest that the expression of ASS1 in villous cytotrophoblast is related to maintaining proliferative phenotype, while ASS1 absence may be involved in promoting the differentiation of villous cytotrophoblast in extravillous cytotrophoblast of cell columns in first trimester placentas.

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Availability of data and materials

The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

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Funding

Funding for this work was provided by Scientific Research Grant from Università Politecnica delle Marche (2020–2021) to D.M. Giovanni Tossetta is a recipient of a fellowship Starting Grant 2018 (SG-2018–12367994) of the Italian Ministry of Health.

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Author notes

  1. Giovanni Tossetta and Daniela Marzioni are co-last authors.

Authors and Affiliations

  1. Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126, Ancona, Italy

    Sonia Fantone, Giovanni Tossetta & Daniela Marzioni

  2. Department of Life Science, University of Siena, 53100, Siena, Italy

    Leonardo Ermini

  3. Cardiovascular Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40128, Bologna, Italy

    Federica Piani

  4. Department of Medical and Surgical Sciences, University of Bologna, 40138, Bologna, Italy

    Federica Piani

  5. Department of Biomedical Sciences, Humanitas University, 20072, Milan, Italy

    Nicoletta Di Simone

  6. IRCCS Humanitas Research Hospital, 20089, Milan, Italy

    Nicoletta Di Simone

  7. Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, 00168, Rome, Italy

    Greta Barbaro

  8. Clinic of Obstetrics and Gynaecology, Department of Clinical Sciences, Università Politecnica delle Marche, Salesi Hospital, Azienda Ospedaliero Universitaria, 60126, Ancona, Italy

    Stefano Raffaele Giannubilo & Giovanni Tossetta

  9. Centre of Epidemiology and Biostatistics, Università Politecnica delle Marche, 60126, Ancona, Italy

    Rosaria Gesuita

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  1. Sonia Fantone
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Contributions

TG and MD contributed to the conception of the study. TG, FP, FS, RG, and MD contributed to the design, performance, and data analysis of the experiments. GSR, DSN, GB, and GS contributed to the sample collection. TG, EL, and MD contributed to the writing of the manuscript. All the authors contributed to the critical revision and final approval of the article.

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Correspondence to Giovanni Tossetta.

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The authors declare that they do not have a conflict of interest.

Ethical approval

Pregnant women gave their written informed consent to collect placental specimens and the procedures followed for the collection of samples were in accordance with the Helsinki Declaration of 1975, as revised in 2013. The permission of the Human Investigation Committee of Marche Region (IT) was granted (protocol number 2019.172; study ID 980; CERM number 172).

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Fantone, S., Ermini, L., Piani, F. et al. Downregulation of argininosuccinate synthase 1 (ASS1) is associated with hypoxia in placental development. Human Cell 36, 1190–1198 (2023). https://doi.org/10.1007/s13577-023-00901-x

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