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PP042. Anti-hypertensive drugs hydralazine, clonidine and labetalol improve trophoblast integration into endothelial cellular networks in vitro

B Xu, F Charlton, A Makris, A Hennessy
Pregnancy Hypertension 2012, 2 (3): 264
26105365

INTRODUCTION: Preeclampsia is an exaggerated maternal inflammatory state with over-expression of placental soluble fms-like tyrosine kinase 1 (sFlt-1). It is also associated with shallow trophoblast invasion and inadequate transformation of uterine spiral arteries. Antihypertensive drugs administrated in preeclampsia to control blood pressure have been reported to regulate placental and circulating cytokine production from women with preeclampsia. Whether they could modulate the interaction between trophoblast and endothelial cells are not investigated.

OBJECTIVES: This study is to examine the effect of pharmacological dose of anti-hypertensive hydralazine, clonidine and labetalol on trophoblast cell integration into inflammatory TNF-a pre-exposed endothelial cellular networks.

METHODS: Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose (0.5ng/ml) inflammatory TNF-a or TNF-a plus sFlt-1 (100ng/ml) for 24hours. These cells were labelled with red fluorescence and seeded on a 24-well culture plate coated with Matrigel. Endothelial tubular structures appeared within 4hours. Green fluorescent-labelled HTR-8/SVneo trophoblast cells were then co-cultured with endothelial cells, with (or without) hydralazine (10μg/ml), clonidine (1.0μg/ml) or labetalol (0.5μg/ml). Red and green fluorescent images were captured after 24hours. Drug effect on HTR-8 cells integration into endothelial cellular networks was quantified by Image Analysis software. The conditioned media were also collected to measure concentrations of free VEGF, PLGF and sFlt-1 by ELISA.

RESULTS: When HTR-8/SVneo trophoblast cells were co-cultured with TNF-a pre-incubated endothelial cells, hydralazine and clonidine can significantly increase the trophoblast integration into endothelial cellular networks. This increase was not seen if co-cultured with normal endothelial cells (without TNF-a pre-incubation) or with TNF-a plus sFlt-1 treated endothelial cells. Labetalol could increase the HTR-8 cell integration into all endothelial cellular networks (with TNF-a and TNF-a plus sFlt-1 treatment). There was no effect of any drug on the trophoblast invasion in the absence of TNF-a. In the conditioned medium, sFlt-1 was down-regulated by hydralazine and clonidine but not by labetalol. A decrease in PLGF was seen in normal endothelial cell groups but not seen in pre-TNF-a or pre-TNF-a plus sFlt-1 endothelial cell groups. VEGF was not changed in all treatment groups.

CONCLUSION: Some anti-hypertensive drugs may improve the cellular interaction between trophoblast and endothelial cells during pregnancy. An increase in sFlt-1 seen in human preeclampsia may deteriorate this effect. Hydralazine and clonidine can reduce the sFlt-1 concentration in the medium. Labetalol could increase trophoblast integration without decreasing sFlt-1, suggesting a mechanism independent of sFlt-1. Our in-vitrodata show that there is a potential effect of these agents on placental maternal arterial modelling. The drug effect on arterial/trophoblast interactions can be related to altered production of sFlt-1.

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