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Hypoxia-induced Downregulation of SRC-3 Suppresses Trophoblastic Invasion and Migration Through Inhibition of the AKT/mTOR Pathway: Implications for the Pathogenesis of Preeclampsia.

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posted on 24.07.2019, 14:01 by C He, N Shan, P Xu, H Ge, Y Yuan, Y Liu, P Zhang, L Wen, F Zhang, L Xiong, C Peng, H Qi, C Tong, PN Baker
Preeclampsia (PE) is characterized by poor placentation, consequent on aberrant extravillous trophoblast (EVT) cell function during placental development. The SRC family of proteins is important during pregnancy, especially SRC-3, which regulates placental morphogenesis and embryo survival. Although SRC-3 expression in mouse trophoblast giant cells has been documented, its role in the functional regulation of extravillous trophoblasts and the development of PE remains unknown. This study found that SRC-3 expression was significantly lower in placentas from PE pregnancies as compared to uncomplicated pregnancies. Additionally, both CoCl2-mimicked hypoxia and suppression of endogenous SRC-3 expression by lentivirus short hairpin RNA attenuated the migration and invasion abilities of HTR-8/SVneo cells. Moreover, we demonstrated that SRC-3 physically interacts with AKT to regulate the migration and invasion of HTR-8 cells, via the AKT/mTOR pathway. We also found that the inhibition of HTR-8 cell migration and invasion by CoCl2-mimicked hypoxia was through the SRC-3/AKT/mTOR axis. Our findings indicate that, in early gestation, accumulation of HIF-1α inhibits the expression of SRC-3, which impairs extravillous trophoblastic invasion and migration by directly interacting with AKT. This potentially leads to insufficient uterine spiral artery remodeling and placental hypoperfusion, and thus the development of PE.

Funding

This work was supported by grants from Chinese Ministry of Science and Technology (2018YFC1004103; 2016YFC1000407), National Natural Sciences Foundation of China (81671488, 81871189; 81771613, 81520108013; 81601304), Chongqing Municipal Education Commission (CXTDX201601014), Science and Technology Commission of Chongqing (cstc2017jcyjBX0045), and Chongqing Entrepreneurship and Innovation Supporting Program for Returned Overseas Students (cx2017104). We would like to acknowledge the support from “111 program” of Ministry of Education P.R.C and State Administration of Foreign Experts Affairs P.R.C.

History

Citation

Scientific Reports, 2019, 9, Article number: 10349

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES

Version

VoR (Version of Record)

Published in

Scientific Reports

Publisher

Nature Research (part of Springer Nature)

eissn

2045-2322

Acceptance date

29/06/2019

Copyright date

2019

Available date

24/07/2019

Publisher version

https://www.nature.com/articles/s41598-019-46699-3

Notes

Supporting data and essential materials for reproducibility of this study are available upon request made to the corresponding authors.

Language

en

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