Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Bern, Switzerland.
School of Medical Technology, Faculty of Medicine and Science, Universidad San Sebastián, Santiago, Chile.
FASEB J. 2024 Feb;38(2):e23431. doi: 10.1096/fj.202301708RR.
Preeclampsia (PE) poses a considerable risk to the long-term cardiovascular health of both mothers and their offspring due to a hypoxic environment in the placenta leading to reduced fetal oxygen supply. Cholesterol is vital for fetal development by influencing placental function. Recent findings suggest an association between hypoxia, disturbed cholesterol homeostasis, and PE. This study investigates the influence of hypoxia on placental cholesterol homeostasis. Using primary human trophoblast cells and placentae from women with PE, various aspects of cholesterol homeostasis were examined under hypoxic and hypoxia/reoxygenation (H/R) conditions. Under hypoxia and H/R, intracellular total and non-esterified cholesterol levels were significantly increased. This coincided with an upregulation of HMG-CoA-reductase and HMG-CoA-synthase (key genes regulating cholesterol biosynthesis), and a decrease in acetyl-CoA-acetyltransferase-1 (ACAT1), which mediates cholesterol esterification. Hypoxia and H/R also increased the intracellular levels of reactive oxygen species and elevated the expression of hypoxia-inducible factor (HIF)-2α and sterol-regulatory-element-binding-protein (SREBP) transcription factors. Additionally, exposure of trophoblasts to hypoxia and H/R resulted in enhanced cholesterol efflux to maternal and fetal serum. This was accompanied by an increased expression of proteins involved in cholesterol transport such as the scavenger receptor class B type I (SR-BI) and the ATP-binding cassette transporter G1 (ABCG1). Despite these metabolic alterations, mitogen-activated-protein-kinase (MAPK) signaling, a key regulator of cholesterol homeostasis, was largely unaffected. Our findings indicate dysregulation of cholesterol homeostasis at multiple metabolic points in both the trophoblast hypoxia model and placentae from women with PE. The increased cholesterol efflux and intracellular accumulation of non-esterified cholesterol may have critical implications for both the mother and the fetus during pregnancy, potentially contributing to an elevated cardiovascular risk later in life.
子痫前期 (PE) 由于胎盘缺氧导致胎儿供氧减少，对母婴的长期心血管健康构成相当大的风险。胆固醇通过影响胎盘功能对胎儿发育至关重要。最近的研究结果表明，缺氧、胆固醇稳态紊乱与 PE 之间存在关联。本研究探讨了缺氧对胎盘胆固醇稳态的影响。使用原代人滋养层细胞和来自患有 PE 的女性的胎盘，在缺氧和缺氧/复氧 (H/R) 条件下检查了胆固醇稳态的各个方面。在缺氧和 H/R 下，细胞内总胆固醇和非酯化胆固醇水平显著增加。这与 HMG-CoA 还原酶和 HMG-CoA 合酶 (调节胆固醇生物合成的关键基因) 的上调以及乙酰辅酶 A-乙酰转移酶 1 (ACAT1) 的下调同时发生，ACAT1 介导胆固醇酯化。缺氧和 H/R 还增加了细胞内活性氧的水平，并上调了缺氧诱导因子 (HIF)-2α 和固醇调节元件结合蛋白 (SREBP) 转录因子的表达。此外，滋养层细胞暴露于缺氧和 H/R 会导致胆固醇向母体和胎儿血清的流出增加。这伴随着胆固醇转运蛋白如清道夫受体 B 类 I 型 (SR-BI) 和三磷酸腺苷结合盒转运蛋白 G1 (ABCG1) 的表达增加。尽管存在这些代谢变化，但胆固醇稳态的关键调节剂丝裂原激活蛋白激酶 (MAPK) 信号几乎没有受到影响。我们的研究结果表明，在滋养层细胞缺氧模型和来自患有 PE 的女性的胎盘的多个代谢点，胆固醇稳态失调。胆固醇流出增加和非酯化胆固醇的细胞内积累可能对母亲和胎儿在怀孕期间都有重要影响，可能导致以后的心血管风险升高。
