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

Crosley, Erin J.; Dunk, Caroline E.; Beristain, Alexander G.; Christians, Julian K.
December 2014
Reproductive Biology & Endocrinology;2014, Vol. 12 Issue 1, p11
Academic Journal
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.


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