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Placental hypoxia-induced alterations in vascular function, morphology, and endothelial barrier integrity

Hypertension Research volume 43, pages 1361–1374 (2020)Cite this article

Abstract

Preeclampsia (PE) is a pregnancy-related disorder characterized by hypertension and proteinuria that affects 3–10% of all pregnancies. Although its pathophysiology remains obscure, placental hypoxia-induced oxidative stress and alterations in vascular function, morphology, and endothelial barrier integrity are considered to play a key role in the development of preeclampsia. In this study, placental villous explants of noncomplicated placentae and BeWo cells were subjected to hypoxia. The effect of placental hypoxic-conditioned medium (HCM) on intraluminal-induced contraction and endothelial barrier integrity in chorionic arteries was investigated using pressure myography. The impact of BeWo cell HCM on endothelial cell viability, reactive oxygen species formation and inflammation was also determined. Alterations in arterial morphology and contractile responsiveness to the thromboxane A2 analog (U46619) after exposure to placental HCM were examined immunohistochemically and by wire myography, respectively. Intraluminal administration of placental HCM induced vasoconstriction and increased the endothelial permeability for KCl, which was concentration-dependently prevented by quercetin. Placental and BeWo cell HCMs decreased endothelial cell viability, increased the production of reactive oxygen species and enhanced the secretion of IL-6 and IL-8. The cross-sectional area of the arterial media was increased upon exposure to placental HCM, which was associated with increased vascular proliferation and contractile responsiveness to U46619, and all of these effects were prevented by the antioxidants quercetin and RRR-α-tocopherol. This study is the first to comprehensively demonstrate the link between factors secreted by placental cells in response to hypoxia and vascular abnormalities and paves the way for new diagnostic approaches and therapies to better protect the maternal vasculature during and after a preeclampsia-complicated pregnancy.

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Acknowledgements

This study was funded by the NUTRIM Graduate Program and supported by the external source: “Fonds gezond geboren”. No additional external funding was received for this study.

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Authors and Affiliations

  1. School of Nutrition and Translational Research in Metabolism (NUTRIM), Department of Pharmacology and Toxicology, Maastricht University Medical Center+, Maastricht, the Netherlands

    Philippe Vangrieken, Alex H. V. Remels, Aalt Bast, Daan Vroomans, Yannick C. W. Pinckers & Frederik J. van Schooten

  2. School for Oncology and Developmental Biology (GROW), Department of Obstetrics and Gynaecology, Maastricht University Medical Center+, Maastricht, the Netherlands

    Salwan Al-Nasiry

  3. School for Cardiovascular Diseases (CARIM), Department of Pharmacology and Toxicology, Maastricht University Medical Center+, Maastricht, the Netherlands

    Ger. M. J. Janssen & Paul M. H. Schiffers

  4. Department of Anatomy and Embryology, Maastricht University Medical Center+, Maastricht, the Netherlands

    Ulrike von Rango

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Contributions

PV designed the study, performed the research, analyzed the data and wrote the paper. AHVR, SA, AB, PMHS, and FJS were involved in the supervision of the research. GMJJ, UR, AC, DV, and YCWP contributed to the experiments and analysis. AHVR and PMHS were involved in conceptualizing the research and writing the manuscript.

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Correspondence to Philippe Vangrieken.

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Vangrieken, P., Remels, A.H.V., Al-Nasiry, S. et al. Placental hypoxia-induced alterations in vascular function, morphology, and endothelial barrier integrity. Hypertens Res 43, 1361–1374 (2020). https://doi.org/10.1038/s41440-020-0528-8

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