Docosahexaenoic acid insufficiency impairs placental angiogenesis by repressing the methylene-bridge fatty acylation of AKT in preeclampsia

Abstract

IntroductionPreeclampsia (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. MethodsCRISPR/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. ResultsCompared 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. DiscussionOur 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.