Inhibition of TGF-β3 restores the invasive capability of extravillous trophoblasts in preeclamptic pregnancies
Isabella Caniggia, … , Martin Post, Stephen J. Lye
Isabella Caniggia, … , Martin Post, Stephen J. Lye
Published June 15, 1999
Citation Information: J Clin Invest. 1999;103(12):1641-1650. https://doi.org/10.1172/JCI6380.
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Article

Inhibition of TGF-β3 restores the invasive capability of extravillous trophoblasts in preeclamptic pregnancies

Abstract

Preeclampsia, the major cause of maternal morbidity and mortality in developed countries, is associated with abnormalities of placenta function due to shallow invasion of the maternal decidua by trophoblasts. Data suggest that TGF-β may play a role in inhibiting trophoblast outgrowth or invasion, or both. We report that placental TGF-β3 expression is high in early pregnancy but falls at around 9 weeks’ gestation. This pattern is inversely correlated with trophoblast outgrowth and fibronectin synthesis, markers of early trophoblast differentiation toward an invasive phenotype. We demonstrate that TGF-β3 is overexpressed in preeclamptic placentae. In contrast to control placentae, explants from preeclamptic pregnancies fail to exhibit spontaneous invasion in vitro. Significantly, antisense-induced inhibition of TGF-β3 expression, and inhibition of TGF-β3 activity with antibodies, induces the formation of columns of trophoblast cells, which migrate out of the explant into the underlying Matrigel. To our knowledge, this is the first demonstration that the hypoinvasive placental phenotype characteristic of preeclampsia can be essentially normalized in vitro by biochemical manipulation. We speculate that a failure to downregulate expression of TGF-β3 at around 9 weeks’ gestation results in shallow trophoblast invasion and predisposes the pregnancy to preeclampsia.

Authors

Isabella Caniggia, Sorina Grisaru-Gravnosky, Maciej Kuliszewsky, Martin Post, Stephen J. Lye

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Figure 1

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Expression of TGF-β isoforms in human placenta in the first trimester of...
Expression of TGF-β isoforms in human placenta in the first trimester of gestation. (a) Message expression of TGF-β isoforms was assessed by low-cycle RT-PCR followed by Southern blot analysis using specific probes for TGF-β1, TGF-β2, TGF-β3, and the control housekeeping gene β-actin. Note that TGF-β3 expression increases at around 7–8 weeks’ gestation and declines thereafter. (b) Expression of TGF-β3 mRNA was also assessed by in situ hybridization to placental sections at 7 and 10 weeks’ gestation with digoxigenin-labeled sense and antisense TGF-β3 riboprobes. Endogenous alkaline phosphatases were blocked by the addition of levamisole. Sections were counterstained with methyl green. Note that TGF-β3 mRNA expression, viewed by blue staining, is high at 7 weeks in chorionic villi and decreases around 10 weeks. Control experiments were performed using sense TGF-β3 riboprobes. ×100. (c) Immunoperoxidase staining of TGF-β3 was performed in placental sections at 8 and 12 weeks’ gestation. Sections of placental tissue of 8 weeks’ gestation show strong positive immunoreactivity viewed as brown staining in the cytotrophoblast, syncytiotrophoblast, and stromal cells of the chorionic villi. Sections of placenta at 12 weeks’ gestation demonstrate low or absent TGF-β3 immunoreactivity in the villi. There is no immunoreactivity when antiserum was preincubated with an excess of TGF-β3 competing peptide (8 weeks, control). ×200.