Effect of placental growth factor in models of experimental preeclampsia and trophoblast invasion.

Placental growth factor (PlGF) is decreased in early gestation of pregnant women who subsequently develop preeclampsia. In this study, pre-emptive treatment with PlGF to prevent preeclampsia was evaluated in an in vivo rodent model of experimental preeclampsia (EPE) induced by TNF-α and in an in vitro model of human first trimester trophoblast invasion. Pregnant C57/BL6 mice were treated with recombinant mouse placental growth factor-2 (rmPlGF-2) 100 μg/kg/day IP from gestational day (gd) 10. Animals had EPE induced by continuous TNF-α infusion on gd13 and were subject to either continuous blood pressure monitoring by radiotelemetry throughout pregnancy or live placenta T2 weighted magnetic resonance imaging (MRI) to demonstrate placental function on gd17. There was no difference in BP (p>0.99), proteinuria (p=0.9) or T2 values on MRI (p=0.9) between control and rmPlGF-2 treated animals. On gd13, animals treated with rmPlGF-2 demonstrated increased placenta PlGF (p=0.01) and toll like receptor-3 (p=0.03) mRNA expression as compared with controls. Fluorescent labelled human uterine microvascular endothelial cells and HTR8/SVNeo cells were co-cultured on Matrigel™ and treated with recombinant human PlGF (rhPlGF) (10 ng/mL) and/or TNF-α (0.5 ng/mL). Trophoblast integration into endothelial networks was reduced by added TNF-α (p=0.006), as was rhPlGF concentration in conditioned media (p<0.0001). Cell integration was not ameliorated by addition of rhPlGF (p>0.9). Although TNF-α induced EPE was not reversed with pre-emptive rmPlGF-2, a further trial of pre-emptive rhPlGF in vivo is required to determine whether the absence of effect of rhPlGF demonstrated in vitro precludes PlGF as a preventative therapy for preeclampsia. This article is protected by copyright. All rights reserved.