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

Reproductive Biology and Endocrinology

Julian K Christians²  Alexander G Beristain³  Caroline E Dunk¹  Erin J Crosley² 

[1] Research Centre for Women’s and Infants Health, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada;Biological Sciences, Simon Fraser University, V5A 1S6 Burnaby, Canada;The Child and Family Research Institute, Vancouver, Canada

关键词: Trophoblast migration;    IGFBP-5;    IGFBP-4;    Insulin-like growth factor-binding proteins;    PAPP-A2;    PAPP-A;    Pappalysins;   

Others  :  1132321
DOI  :  10.1186/1477-7827-12-123

 received in 2014-10-08, accepted in 2014-11-26,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Crosley et al.; licensee BioMed Central Ltd.

【 图 表 】

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