School for Cardiovascular Diseases, Department of Internal Medicine (P.V., S.N., J.L.J.M.S., C.G.S.), Maastricht University Medical Center+, the Netherlands.
School for Oncology and Developmental Biology, Department of Obstetrics and Gynaecology (S.A.-N., E.J., M.E.A.S.), Maastricht University Medical Center+, the Netherlands.
Hypertension. 2024 Jul;81(7):1537-1549. doi: 10.1161/HYPERTENSIONAHA.123.22633. Epub 2024 May 16.
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.
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-(carboxymethyl)lysine [CML], N-(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.
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.
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.
子痫前期是一种多方面的综合征，包括母体血管功能障碍。我们假设子痫前期胎盘糖酵解和缺氧增加会导致甲基乙二醛 (MGO) 水平升高，从而导致血管功能障碍。
从正常妊娠和子痫前期妊娠中收集血浆样本和胎盘。正常胎盘和滋养细胞 (BeWo) 暴露于缺氧环境中。使用液相色谱-串联质谱法定量测定反应性二羰基 MGO 和晚期糖基化终产物 (N-(羧甲基)赖氨酸 [CML]、N-(羧乙基)赖氨酸 [CEL] 和 MGO 衍生的羟咪唑啉 [MG-H])。测量 GLO1（甘油醛-3-磷酸脱氢酶）的活性，即解毒 MGO 的酶。使用线/压肌描记法评估 MGO 对血管功能的影响。探索 MGO 清除剂槲皮素和线粒体特异性抗氧化剂米托醌甲磺酸盐 (MitoQ) 的治疗潜力。
子痫前期胎盘中的 MGO、CML、CEL 和 MG-H2 水平升高（分别增加 36%、36%、25%和 22%）。子痫前期胎盘和缺氧暴露胎盘中的 GLO1 活性降低（分别减少 12%和 16%）。MGO 清除剂槲皮素减轻了缺氧诱导的胎盘 MGO 积累。滋养细胞被鉴定为 MGO 的主要来源。缺氧暴露的 BeWo 细胞中的 GLO1 活性也降低（减少 26%）。早在妊娠 12 周时，母体血浆中 CML 和 MGO 衍生的 MG-H1 浓度就增加了（分别增加 16%和 17%）。MGO 损害内皮屏障功能，MitoQ 减轻了这种作用，并增强了血管对血栓烷 A2 的反应性。
本研究揭示了子痫前期胎盘 MGO 的积累以及暴露于缺氧环境时，MGO 如何导致血管损伤，并强调了血浆 CML 和 MG-H1 水平作为子痫前期有前途的早期生物标志物。
