Zinc improves learning and memory abilities of fetal growth restriction rats and promotes trophoblast cell invasion and migration via enhancing STAT3-MMP-2/9 axis activity.

Lu Zong,Ye Lv,Xiaohua Wei,Wenli Gou,Pu Huang

doi:10.18632/oncotarget.23122

Abstract

Fetal growth restriction (FGR) is a well-known risk factor for cognitive dysfunction, especially for learning and memory abilities. However, knowledge about prevention and treatment methods of learning and memory abilities of fetal are limit. Here, Morris water maze and passive avoidance tests showed zinc supplementation could protect the impairment of the learning and memory abilities caused by FGR. As accumulating evidence suggested that insufficiency of placental trophoblast cell invasion was closely related to FGR fetal neurodevelopmental dysplasia, we further explored the relationship between zinc supplementation during pregnancy and placental trophoblast. Microarray identified 346 differently expressed genes in placental tissues with and without zinc supplementation, and GO and KEGG analyses showed these differently expressed genes were highly enriched in cell invasion and migration and STAT3 pathway. Protein-protein interaction(PPI) analysis found that STAT3 interacted with matrix metalloproteinase-2/9 (MMP-2/9). In vivo, western blot results authenticated that the expression levels of phospho-STAT3, STAT3, MMP-2 and MMP-9 were up-regulated in placental tissues after zinc treatment. To validate whether zinc could promotes trophoblast cell invasion and migration via enhancing STAT3-MMP-2/9 activity. In vitro, Transwell assay was performed, and we observed that abilities of invasion and migration were obviously increased in zinc treated trophoblast cells. And phospho-STAT3, STAT3, MMP-2 and MMP-9 expression levels were correspondingly increased in zinc treated trophoblast cells, which were dose-dependent. Moreover, gain–of-function and loss-of-function of STAT3 confirmed that zinc promotes cell invasion and migration via regulating STAT3 mediated up-regulation of MMP-2/9 activity. We propose that activation of MMP-2/9 mediated by STAT3 may contribute to invasion and migration of trophoblast cells, which improved neurodevelopmental impairment of FGR rats probably via contributing to placental development. Our findings are the first to show a possible mechanism of reversing neurodevelopmental impairment of FGR rats by zinc supplementation, holding promise for the development of novel therapeutic modalities for learning and memory abilities impairment caused by FGR.

Highlights

Fetal growth restriction (FGR) defined as estimated fetal weight below the 10th percentile, which could lead to a variety of diseases include neonatal encephalopathy, cerebral palsy, sepsis, seizures, respiratory distress, etc [1]
There is considerable evidence to support that learning and memory abilities impairment of FGR rats associated with placenta, especially for the deficiency of trophoblast cell invasion and migration [1]
In the present study we firstly showed that zinc supplement improved memory and learning abilities of FGR rats, and increased the abilities of invasion and migration of trophoblast cells

Summary

Introduction

Fetal growth restriction (FGR) defined as estimated fetal weight below the 10th percentile, which could lead to a variety of diseases include neonatal encephalopathy, cerebral palsy, sepsis, seizures, respiratory distress, etc [1]. Thereinto, cognitive dysfunction is primary influencen on fetal [2], mainly manifested on learning and memory ability [3]. Children from pregnancies with FGR have demonstrated significantly lower academic achievement in school as well as lower professional achievement in adulthood [1]. It’s vital to avoid neurodevelopment impairment caused by FGR. Fetal growth is a complex process involving maternal, placental and fetal factors [4].

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Results

Conclusion