Endothelin-1 stimulates the proliferation and invasion of first trimester trophoblastic cells in vitro--a possible role in the etiology of pre-eclampsia?

BACKGROUND: Endothelin-1 is a potent mitogen and stimulates cell chemokinesis, but these properties have not been investigated in the placenta. Trophoblastic cells from pre-eclamptic pregnancies have a reduced invasive potency and secrete less endothelin-1 than those from normal pregnancies. The present study tested the hypothesis that endothelin-1 affects trophoblast proliferation and invasion.
METHODS: Trophoblastic cells were isolated from 37 placentae of normal human pregnancies at week 12 by dispastrypsin digestion and subsequently immunopurified to remove nontrophoblastic components. The effects of 5, 10, and 20 nmol/mL endothelin-1 on proliferation and invasion were determined after 24 and 72 hours, respectively, by fluorescence-activated pulse cytometry (FACS) analysis, by measuring DNA synthesis using two different methods and by a Matrigel invasion assay.
RESULTS: All cell preparations uniformly responded to 10 nmol/mL by increased proliferation, owing to a greater proportion of cells in the S-phase of their cell cycle, and invasion. The effects were more pronounced after 24 hours than after 72 hours, by which time cell viability, as measured by the secretion of human chorionic gonadotropin (hCG-beta), had deteriorated. The nonselective receptor antagonist PD 142893 inhibited both endothelin-1 effects.
CONCLUSION: Endothelin-1 is a mitogenic stimulus for first trimester trophoblastic cells in vitro. The stimulation of cellular invasion represents a novel effect of endothelin-1. We suggest the implication of endothelin-1 in proliferation and invasion of trophoblast and tumour cells and hypothesize a possible role in the etiology of pre-eclampsia.