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Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2014

Open Access 01-12-2014 | Research

IGFBP-4 and −5 are expressed in first-trimester villi and differentially regulate the migration of HTR-8/SVneo cells

Authors: Erin J Crosley, Caroline E Dunk, Alexander G Beristain, Julian K Christians

Published in: Reproductive Biology and Endocrinology | Issue 1/2014

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Abstract

Background

Adverse gestational outcomes such as preeclampsia (PE) and intrauterine growth restriction (IUGR) are associated with placental insufficiency. Normal placental development relies on the insulin-like growth factors -I and -II (IGF-I and -II), in part to stimulate trophoblast proliferation and extravillous trophoblast (EVT) migration. The insulin-like growth factor binding proteins (IGFBPs) modulate the bioavailability of IGFs in various ways, including sequestration, potentiation, and/or increase in half-life. The roles of IGFBP-4 and −5 in the placenta are unknown, despite consistent associations between pregnancy complications and the levels of two IGFBP-4 and/or −5 proteases, pregnancy-associated plasma protein -A and -A2 (PAPP-A and PAPP-A2). The primary objective of this study was to elucidate the effects of IGFBP-4 and −5 on IGF-I and IGF-II in a model of EVT migration. A related objective was to determine the timing and location of IGFBP-4 and −5 expression in the placental villi.

Methods

We used wound healing assays to examine the effects of IGFBP-4 and −5 on the migration of HTR-8/SVneo cells following 4 hours of serum starvation and 24 hours of treatment. Localization of IGFBP-4, −5 and PAPP-A2 was assessed by immunohistochemical staining of first trimester placental sections.

Results

2 nM IGF-I and -II each increased HTR-8/SVneo cell migration with IGF-I increasing migration significantly more than IGF-II. IGFBP-4 and −5 showed different levels of inhibition against IGF-I. 20 nM IGFBP-4 completely blocked the effects of 2 nM IGF-I, while 20 nM IGFBP-5 significantly reduced the effects of 2 nM IGF-I, but not to control levels. Either 20 nM IGFBP-4 or 20 nM IGFBP-5 completely blocked the effects of 2 nM IGF-II. Immunohistochemistry revealed co-localization of IGFBP-4, IGFBP-5 and PAPP-A2 in the syncytiotrophoblast layer of first trimester placental villi as early as 5 weeks of gestational age.

Conclusions

IGFBP-4 and −5 show different levels of inhibition on the migration-stimulating effects of IGF-I and IGF-II, suggesting different roles for PAPP-A and PAPP-A2. Moreover, co-localization of the pappalysins and their substrates within placental villi suggests undescribed roles of these molecules in early placental development.
Appendix
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Metadata
Title
IGFBP-4 and −5 are expressed in first-trimester villi and differentially regulate the migration of HTR-8/SVneo cells
Authors
Erin J Crosley
Caroline E Dunk
Alexander G Beristain
Julian K Christians
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2014
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/1477-7827-12-123

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