Obstetrics and Gynecology Hospital of Fudan University, Fangxie Road 419, Huangpu District, Shanghai, China; The Institute of Biomedical Science, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
Department of Obstetrics, Shenzhen Maternal and Child Health Care Hospital Affiliated to Southern Medical University, Shenzhen, China.
Placenta. 2024 Sep 26;155:100-112. doi: 10.1016/j.placenta.2024.08.012. Epub 2024 Aug 22.
Preeclampsia (PE), characterised by hypertension in pregnancy, is regarded as a placental metabolism-related syndrome affecting 5-8% of pregnancies worldwide. The insufficiency of polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), is a causative factor of PE pathogenesis. However, its molecular aetiology is yet to be comprehensively elucidated.
CRISPR/Cas9 was used to construct Fads2 knockout mice. Gas chromatography-mass spectrometry was used to detect placental fatty acid levels. Gene Expression Omnibus was used to analyze placental FADS2 mRNA levels. CCK-8 assay was used to assess cell growth capacity. Cell migration and invasion abilities were measured by transwell and wound healing assay. Tube forming assay was used to test angiogenesis ability. The co-immunoprecipitation assay was used to validate interactions between two proteins. AKT inhibitor MK-2206 and methylene-bridge fatty acylation inhibitor tryptophan were used to rescue experiments.
Compared to those in women with normal pregnancies, the DHA levels in the placentas of patients with PE decreased with the downregulation of FADS2, the key desaturase in the synthesis of PUFAs. Pregnant Fads2 mice exhibited PE-like symptoms, including proteinuria and elevated systolic arterial blood pressure, due to defective placental angiogenesis. Mechanistically, FADS2 knockdown in trophoblasts decreased cellular DHA levels and repressed the methylene-bridge fatty-acylation of AKT, inhibiting AKT-VEGFA signalling, which is crucial for angiogenesis.
Our results suggest that placental DHA insufficiency downregulates placental angiogenesis via inhibiting fatty acylating AKT and AKT-VEGFA signalling, a novel insight into abnormal fatty acid metabolism in PE.
子痫前期（PE）以妊娠高血压为特征，被认为是一种与胎盘代谢相关的综合征，影响全球 5-8%的妊娠。多不饱和脂肪酸（PUFAs）如二十二碳六烯酸（DHA）的不足是 PE 发病机制的一个原因。然而，其分子发病机制尚未得到全面阐明。
使用 CRISPR/Cas9 构建 Fads2 敲除小鼠。气相色谱-质谱联用检测胎盘脂肪酸水平。基因表达综合数据库分析胎盘 FADS2 mRNA 水平。CCK-8 法评估细胞生长能力。通过 Transwell 和划痕愈合实验测定细胞迁移和侵袭能力。管形成实验检测血管生成能力。共免疫沉淀实验验证两种蛋白质之间的相互作用。AKT 抑制剂 MK-2206 和亚甲基桥脂肪酸酰化抑制剂色氨酸用于挽救实验。
与正常妊娠妇女相比，PE 患者胎盘 DHA 水平降低，FADS2 下调，这是 PUFAs 合成的关键去饱和酶。妊娠 Fads2 小鼠出现 PE 样症状，包括蛋白尿和收缩压升高，这是由于胎盘血管生成缺陷所致。机制上，滋养细胞中 FADS2 的敲低降低了细胞内 DHA 水平，并抑制了 AKT 的亚甲基桥脂肪酸酰化，从而抑制了 AKT-VEGFA 信号通路，这对血管生成至关重要。
我们的结果表明，胎盘 DHA 不足通过抑制脂肪酸酰化 AKT 和 AKT-VEGFA 信号通路下调胎盘血管生成，这为 PE 中异常脂肪酸代谢提供了新的见解。
