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Vitamin D insufficiency/deficiency has been linked to an increased risk of preeclampsia. Impaired placental amino acid transport is suggested to contribute to abnormal fetal intrauterine growth in pregnancies complicated by preeclampsia. However, if vitamin D-regulated amino acid transporter is involved in the pathophysiologic mechanism of preeclampsia has not been clarified yet. The aberrant expression of key isoform of L-type amino acid transporter LAT1 was determined by western blot and immunohistochemistry in the placenta from normotensive and preeclamptic pregnancies. The role for vitamin D on placental LAT1 expression was investigated through the exposure of HTR-8/SVneo human trophoblast cells to the biologically active 1,25(OH) 2 D 3 and the oxidative stress-inducer cobalt chloride (CoCl 2 ). Our results showed that placental LAT1 expression was reduced in women with preeclampsia compared to normotensive pregnancies, which was associated with decreased expression of vitamin D receptor (VDR). 1,25(OH) 2 D 3 significantly upregulated LAT1 expression in placental trophoblasts, and also prevented the decrease of mTOR activity under CoCl 2 -induced oxidative stress. siRNA targeting VDR significantly attenuated 1,25(OH) 2 D 3 -stimulated LAT1 expression and mTOR signaling activity. Moreover, treatment of rapamycin specifically inhibited the activity of mTOR signaling and resulted in decrease of LAT1 expression. In conclusion, LAT1 expression was downregulated in the placenta from women with preeclampsia. 1,25(OH) 2 D 3 /VDR could stimulate LAT1 expression, which was likely mediated by mTOR signaling in placental trophoblasts. Regulation on placental amino acid transport may be one of the mechanisms by which vitamin D affects fetal growth in preeclampsia., (© 2022. The Author(s).)

Vitamin D insufficiency or deficiency during pregnancy has been associated with an increased risk of preeclampsia. Increased placental cyclooxygenase-2 (COX-2) activity was proposed to contribute to the inflammatory response in preeclampsia. This study was to investigate if vitamin D can benefit preeclampsia by inhibiting placental COX-2 expression. Placenta tissues were obtained from 40 pregnant women (23 normotensive and 17 preeclampsia). miR-26b-5p expression was assessed by quantitative PCR. Vitamin D receptor (VDR) expression and COX-2 expression were determined by immunostaining and Western blot. HTR-8/SVneo trophoblastic cells were cultured in vitro to test anti-inflammatory effects of vitamin D in placental trophoblasts treated with oxidative stress inducer CoCl 2 . 1,25(OH) 2 D 3 was used as bioactive vitamin D. Our results showed that reduced VDR and miR-26b-5p expression, but increased COX-2 expression, was observed in the placentas from women with preeclampsia compared to those from normotensive pregnant women. Transient overexpression of miR-26b-5p attenuated the upregulation of COX-2 expression and prostaglandin E 2 (PGE 2 ) production induced by CoCl 2 in placental trophoblasts. 1,25(OH) 2 D 3 treatment inhibited CoCl 2 -induced upregulation of COX-2 in placental trophoblasts. Moreover, miR-26b-5p expression were significantly upregulated in cells treated with 1,25(OH) 2 D 3 , but not in cells transfected with VDR siRNA. Conclusively, downregulation of VDR and miR-26b-5p expression was associated with upregulation of COX-2 expression in the placentas from women with preeclampsia. 1,25(OH) 2 D 3 could promote miR-26b-5p expression which in turn inhibited COX-2 expression and PGE 2 formation in placental trophoblasts. The finding of anti-inflammatory property by vitamin D through promotion of VDR/miR-26b-5p expression provides significant evidence that downregulation of vitamin D/VDR signaling could contribute to increased inflammatory response in preeclampsia.

Alterations in placental transport may contribute to abnormal fetal intrauterine growth in pregnancies complicated by diabetes, but it is not clear whether the placental amino acid transport system is altered in diabetic pregnancies. We therefore studied the changes in the expressions of placental amino acid transporters in a rat model of diabetes induced by streptozotocin, and tested the effects of hyperglycemia on trophoblast amino acid transporter in vitro. Our results showed that the expressions for key isoforms of system L amino acid transporters were significantly reduced in the placentas of streptozotocin-induced diabetic pregnant rats, which was associated with the decreased birthweight in the rats. A decreased placental efficiency and decreased placental mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity were also found in the rat model. In addition, hyperglycemia in vitro could inhibit amino acid transporter expression and mTORC1 activity in human trophoblast. Inhibition of mTORC1 activity led to reduced amino acid transporter expression in placental trophoblast. We concluded that reduced placental mTORC1 activity during pregnancy resulted in decreased placental amino acid transporter expression and, subsequently, contributed to fetal intrauterine growth restriction in pregnancies complicated with diabetes.

Preeclampsia is a placentally induced syndrome with diverse clinical presentation that currently has no cure. Oxidative stress is a potent inducer of placental dysfunction. The apelin receptor (APJ) system is a pleiotropic pathway with a potential for therapeutic targeting in preeclampsia. This study examines the alteration of circulating apelin levels and placental APJ expression in preeclampsia and investigates whether apelin/APJ system can protect placental trophoblast from hypoxia-induced oxidative stress injury through PI3K/AKT signaling pathway. Our results confirmed that maternal apelin concentration was increased in women with preeclampsia, but APJ expression was reduced in the preeclamptic placentas. Apelin-13 treatment not only specifically attenuated CoCl 2 -induced superoxide production, but also prevented CoCl 2 -induced reduction of SOD activity and SOD1 expression. In addition, apelin-13 suppressed CoCl 2 -induced apoptosis by increasing the expression of bcl-2/bax ratio and by decreasing the expression of active caspase-3 in placental trophoblasts. Furthermore, we found that apelin-13 binding APJ activated the PI3K and AKT kinases and inhibition of PI3K kinase significantly blocked the anti-oxidative effects of apelin-13 in placental trophoblasts. Decrease of placental APJ expression is associated with oxidative stress-induced placental dysfunction in preeclampsia, and increased circulating apelin could be a moderately successful marker to differentiate subjects with preeclampsia from healthy pregnant women. Inhibition of superoxide production and caspase-3 cleavage, together with upregulation of SOD activity/expression and bcl-2/bax ratio, could be the potential molecular mechanisms by which apelin-13/APJ protects placental trophoblasts from oxidative stress injury. [Display omitted] • Women with PE have increased concentration of apelin in the blood and decreased expression of apelin receptor in the placenta. • Apelin-13/APJ axis alleviates oxidative stress by reducing ROS production and enhancing SOD activity in trophoblast cells. • Apelin-13/APJ axis exerts anti-oxidative stress properties by activating the PI3K/AKT cascade in trophoblast cells. [ABSTRACT FROM AUTHOR]