Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor‐α inhibited endothelial nitric oxide synthase expression in endothelial‐trophoblast cellular networks

Abstract

Medications used to control hypertension in pregnancy also improve trophoblast and endothelial cellular interaction in vitro. Tumour necrosis factor-α (TNF-α) inhibits trophoblast and endothelial cellular interactions and simultaneously decreases endothelial nitric oxide synthase (eNOS) expression. This study investigated whether antihypertensive medications improved these cellular interactions by modulating eNOS and inducible nitric oxide synthase (iNOS) expression. Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose TNF-α (0.5 ng/mL) or TNF-α plus soluble fms-like tyrosine kinase-1 (sFlt-1) (100 ng/mL). The endothelial cells were cultured on Matrigel. After endothelial cellular networks appeared, trophoblast derived HTR-8/SVneo cells were co-cultured in the presence of clinically relevant doses of methyldopa, labetalol, hydralazine or clonidine for 24 hours. Cells were retrieved from the Matrigel to extract mRNA and eNOS and iNOS expression were examined by quantitative PCR. Methyldopa, labetalol, hydralazine and clonidine reversed the inhibitory effect of TNF-α on eNOS mRNA expression. After pre-incubating endothelial cells with TNF-α and sFlt-1, all the medications except methyldopa lost their effect on eNOS mRNA expression. In the absence of TNF-α, antihypertensive medications did not change eNOS expression. The mRNA expression of iNOS was not affected by TNF-α or any medications. This study shows that selected antihypertensive medications used in the treatment of hypertension in pregnancy increase eNOS expression in vitro when induced by the inflammatory TNF-α. The anti-angiogenic molecule sFlt-1 may antagonise the potential benefit of these medications by interfering with the NOS pathway.

Effect of magnesium sulfate combined with labetalol on serum sFlt‑1/PlGF ratio in patients with early‑onset severe pre‑eclampsia

“…For example, labetalol could act on sFlt-1 to promote the integration of trophoblast cells. The possible reason for this function may be the fact that labetalol can directly act on vascular smooth muscle cells and improve the function of vascular endothelium by regulating the secretion of inflammatory factors in the blood vessels (34). The present study further investigated the role of sFlt-1, PlGF, and their ratio in the treatment of ES-PE patients.…”

Effects of metoprolol, methyldopa, and nifedipine on endothelial progenitor cells in patients with gestational hypertension and preeclampsia

“…Nifedipine blocks the calcium channel, and thus affects diverse cell signals such as the PPAR‐β/‐γ‐dependent signal, which is correlated with increased eNOS activity and NO production in cultured endothelial cells and hypertensive patients . Methyldopa is effective against NO reduction caused by TNF‐α and sFlt‐1 in a co‐culture system of human uterine myometrial microvascular endothelial cells and trophoblast cells . Moreover, methyldopa improved NO synthesis in pregnant Wistar rats that received L‐NAME, a NO synthase inhibitor .…”

Cyclin G2 Is Involved in the Proliferation of Placental Trophoblast Cells and Their Interactions with Endothelial Cells

“…To assess the ability of HTR8/SVneo cells to integrate into endothelium, green fluorescent trophoblasts and red fluorescent endothelial cells were co-cultured as described, with minor modifications [ 35 – 38 ]. Briefly, 24-well culture plates were coated with undiluted Matrigel (BD Biosciences) (300 μl/well) and polymerized at 37°C for 30 min.…”