Abstract
Preeclampsia (PE) complicates 2-8% of pregnancies worldwide. In women with diabetes, the risk for PE is substantially increased by approximately 4 fold. Evidence indicates that an increased release of two anti-angiogenic factors, soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng) from placental trophoblasts into the maternal circulation promotes endothelial dysfunction associated with PE. In this study, we investigated sFlt-1 and sEng release from the human placental trophoblast cell line, HTR8/SVneo, in response to modified lipoproteins and/or elevated glucose. HTR8/SVneo cells were exposed to native low-density lipoprotein (N-LDL) vs. ’highly-oxidized glycated’ LDL (HOG-LDL) (50 µg protein/ml) for 24h, with and without pre-treatment with 30mM glucose for 72h. The mRNA expressions of sFlt-1 isoforms (sFlt-1-i13, sFlt-1-e15a), endoglin and MMP-14 were measured by RT-PCR, and levels of sFlt-1 and sEng in cell supernatant were determined by ELISA. Compared with N-LDL, HOG-LDL increased the mRNA expression of sFlt-1-i13 (2.0 fold, p<0.05), sFlt-1-e15a (1.9 fold, p<0.01), endoglin (1.5 fold, p<0.05) and MMP-14 (1.8 fold, p<0.05). HOG-LDL increased the levels of sFlt-1 and sEng proteins in the supernatant (2.9 fold, p<0.and 3.6 fold, p<0.01, respectively). High glucose alone had no significant effect on sFlt-1 and sEng expressions; however, pre-treatment of high glucose potentiated the effects of HOG-LDL: the supernatant levels of sFlt-1 and sEng were increased by 1.5 fold and 1.8 fold, respectively, compared to HOG-LDL treatment alone (p<0.for both). Exposure of trophoblasts to modified lipoproteins (which accumulate in the tissues of patients with diabetes due to vascular leakage) may contribute to the development of PE in diabetes, which is amplified by the presence of high glucose. These findings may explain, in part, the high risk of PE in women with diabetes. Disclosure R.H. McLeese: None. J. Zhao: None. J. Yu: None. D. Brazil: None. T. Lyons: None.
Highlights
Pre-e clampsia (PE) is increased ~4-fold by maternal diabetes
What are the new findings? ►► In cultured human trophoblasts, modified low-density lipoprotein (LDL) diminished cell viability, increased release of soluble fms- like tyrosine kinase and soluble endoglin and induced barrier dysfunction. ►► Effects of modified LDL were amplified by high glucose concentrations, which alone had no effect. ►► Intravillous modified LDL is present in human term placentae
In JAR cells, soluble endoglin (sENG) release increased sixfold (n=4, p
Summary
Pre-e clampsia (PE) is increased ~4-fold by maternal diabetes. Elevated plasma antiangiogenic factors, soluble fms-like tyrosine kinase (sFLT-1) and soluble endoglin (sENG), precede PE onset. ►► In cultured human trophoblasts, modified LDL diminished cell viability, increased release of soluble fms- like tyrosine kinase (sFLT-1) and soluble endoglin (sENG) and induced barrier dysfunction. Mortality; it is ~4-f old more frequent in women with diabetes (~20% vs 5%).[1] The pathogenesis of PE is poorly understood, but in the second trimester, elevated maternal plasma concentrations of antiangiogenic factors, soluble fms-like tyrosine kinase (sFLT-1) and soluble endoglin (sENG), are predictive.[2 3] In women with type 1 diabetes, elevated sFLT-1 predicts PE as expected, but sENG appears to rise excessively in all women with diabetes, perhaps explaining their susceptibility.[4] sFLT-1 is formed by alternative splicing[5]; the BMJ Open Diab Res Care 2021;9:e001696. In women with type 1 diabetes, elevated sFLT-1 predicts PE as expected, but sENG appears to rise excessively in all women with diabetes, perhaps explaining their susceptibility.[4] sFLT-1 is formed by alternative splicing[5]; the BMJ Open Diab Res Care 2021;9:e001696. doi:10.1136/bmjdrc-2020-001696
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