TITLE

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

AUTHOR(S)
Crosley, Erin J.; Dunk, Caroline E.; Beristain, Alexander G.; Christians, Julian K.
PUB. DATE
December 2014
SOURCE
Reproductive Biology & Endocrinology;2014, Vol. 12 Issue 1, p11
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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, colocalization of the pappalysins and their substrates within placental villi suggests undescribed roles of these molecules in early placental development.
ACCESSION #
100366523

 

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