In-vitro study of the effect of anti-hypertensive drugs on placental hormones and angiogenic proteins synthesis in pre-eclampsia.

Eric Jauniaux,Subrata Gangooly,Shanthi Muttukrishna

doi:10.1371/journal.pone.0107644

Eric Jauniaux, Subrata Gangooly + Show 1 more

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https://doi.org/10.1371/journal.pone.0107644

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Abstract

IntroductionAntihypertensive drugs lower the maternal blood pressure in pre-eclampsia (PE) by direct or central vasodilatory mechanisms but little is known about the direct effects of these drugs on placental functions.ObjectiveThe aim of our study is to evaluate the effect of labetolol, hydralazine, α-methyldopa and pravastatin on the synthesis of placental hormonal and angiogenic proteins know to be altered in PE.DesignPlacental villous explants from late onset PE (n = 3) and normotensive controls (n = 6) were cultured for 3 days at 10 and 20% oxygen (O2) with variable doses anti-hypertensive drugs. The levels of activin A, inhibin A, human Chorionic Gonadotrophin (hCG), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured in explant culture media on day 1, 2 and 3 using standard immunoassays. Data at day 1 and day 3 were compared.ResultsSpontaneous secretion of sEndoglin and sFlt-1 were higher (p<0.05) in villous explants from PE pregnancies compared to controls. There was a significant time dependant decrease in the secretion of sFlt-1 and sEndoglin in PE cases, which was seen only for sFlt-1 in controls. In both PE cases and controls the placental protein secretions were not affected by varying doses of anti-hypertensive drugs or the different O2 concentration cultures, except for Activin, A which was significantly (p<0.05) higher in controls at 10% O2.InterpretationOur findings suggest that the changes previously observed in maternal serum hormones and angiogenic proteins level after anti-hypertensive treatment in PE could be due to a systemic effect of the drugs on maternal blood pressure and circulation rather than a direct effect of these drugs on placental biosynthesis and/or secretion.

Highlights

Antihypertensive drugs lower the maternal blood pressure in pre-eclampsia (PE) by direct or central vasodilatory mechanisms but little is known about the direct effects of these drugs on placental functions
Interpretation: Our findings suggest that the changes previously observed in maternal serum hormones and angiogenic proteins level after anti-hypertensive treatment in PE could be due to a systemic effect of the drugs on maternal blood pressure and circulation rather than a direct effect of these drugs on placental biosynthesis and/or secretion
Our study shows that in vitro secretion of angiogenic proteins soluble endoglin (sEng) and soluble fms-like tyrosine kinase-1 (sFlt-1) is higher in villous tissue obtained at the time of elective caesarean section performed at term in women presenting with late PE compared to normal controls obtained under the same experimental condition

Summary

Introduction

Antihypertensive drugs lower the maternal blood pressure in pre-eclampsia (PE) by direct or central vasodilatory mechanisms but little is known about the direct effects of these drugs on placental functions. Placental-related diseases of pregnancy are almost unique to the human species and affect around a third of human pregnancies [2] These diseases include mainly miscarriages and pre-eclampsia (PE), which are respectively at the opposite end of a spectrum of major disorders of the development of the utero-placental interface. In PE, placentation is sufficient to allow partial development of the placenta but too shallow for complete development of the uteroplacental circulation and normal fetal growth during the second half of pregnancy [3,4]. Chronic oxidative stress inside the placenta leads to progressive damage of the villous tissue, fetal growth restriction and to diffuse maternal endothelial cell dysfunction and clinical PE [2,6,9,10]

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