Placental Methylglyoxal in Preeclampsia: Vascular and Biomarker Implications

Philippe Vangrieken; Salwan Al-Nasiry; Alex H V Remels; Paul M H Schiffers; E Janssen; Stefanie Nass; Jean L J M Scheijen; Marc E A Spaanderman; Casper G Schalkwijk

doi:10.1161/HYPERTENSIONAHA.123.22633

Placental Methylglyoxal in Preeclampsia: Vascular and Biomarker Implications

Hypertension. 2024 May 16. doi: 10.1161/HYPERTENSIONAHA.123.22633. Online ahead of print.

Authors

Philippe Vangrieken¹, Salwan Al-Nasiry², Alex H V Remels³, Paul M H Schiffers⁴, E Janssen², Stefanie Nass¹, Jean L J M Scheijen¹, Marc E A Spaanderman², Casper G Schalkwijk¹

Affiliations

¹ School for Cardiovascular Diseases, Department of Internal Medicine, Maastricht University Medical Center+, the Netherlands. (P.V., S.N., J.L.J.M.S., C.G.S.).
² School for Oncology and Developmental Biology, Department of Obstetrics and Gynaecology, Maastricht University Medical Center+, the Netherlands. (S.A.-N., E.J., M.E.A.S.).
³ School of Nutrition and Translational Research in Metabolism, Department of Pharmacology and Toxicology, Maastricht University Medical Center+, the Netherlands. (A.H.V.R.).
⁴ School for Cardiovascular Diseases, Department of Pharmacology and Toxicology, Maastricht University Medical Center+, the Netherlands. (P.M.H.S.).

PMID: 38752345
DOI: 10.1161/HYPERTENSIONAHA.123.22633

Abstract

Background: Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction.

Methods: Plasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (N^ε-(carboxymethyl)lysine [CML], N^ε-(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored.

Results: MGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (-12%) and hypoxia-exposed placentas (-16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (-26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2.

Conclusions: This study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia.

Keywords: biomarkers; glycation end products, advanced; placenta; pre-eclampsia; trophoblasts.