Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6β: implications for the pathophysiology of human pregnancy complications

摘要

Low maternal circulating concentrations of placental growth factor (PlGF) are one of the hallmarks of human pregnancy complications, including fetal growth restriction (FGR) and early‐onset pre‐eclampsia (PE). Currently, PlGF is used clinically with other biomarkers to screen for high‐risk cases, although the mechanisms underlying its regulation are largely unknown. Placental endoplasmic reticulum (ER) stress has recently been found to be elevated in cases of FGR, and to an even greater extent in early‐onset PE complicated with FGR. ER stress activates the unfolded protein response (UPR); attenuation of protein translation and a reduction in cell growth and proliferation play crucial roles in the pathophysiology of these complications of pregnancy. In this study, we further identified that ER stress regulates release of PlGF. We first observed that down‐regulation of PlGF protein was associated with nuclear localization of ATF4, ATF6α and ATF6β in the syncytiotrophoblast of placentae from style="fixed-case">PE patients. Transcript analysis showed a decrease of style="italic-in-any-context"> style="fixed-case">PlGF style="fixed-case">mRNA, and an increase from genes encoding those style="fixed-case">UPR transcription factors in placentae from cases of early‐onset style="fixed-case">PE, but not of late‐onset (>34 weeks) style="fixed-case">PE, compared to term controls. Further investigations indicated a strong correlation between style="italic-in-any-context"> style="fixed-case">ATF4 and style="italic-in-any-context"> style="fixed-case">PlGF style="fixed-case">mRNA levels only ( style="italic-in-any-context">r = − 0.73, style="italic-in-any-context">p < 0.05). These results could be recapitulated in trophoblast‐like cells exposed to chemical inducers of style="fixed-case">ER stress or hypoxia–reoxygenation. The stability of style="italic-in-any-context"> style="fixed-case">PlGF transcripts was unchanged. The use of small interfering style="fixed-case">RNA specific for transcription factors in the style="fixed-case">UPR pathways revealed that style="fixed-case">ATF4 and style="fixed-case">ATF6β, but not style="fixed-case">ATF6α, modulate style="italic-in-any-context"> style="fixed-case">PlGF transcription. To conclude, style="fixed-case">ATF4 and style="fixed-case">ATF6β act synergistically in the negative regulation of style="italic-in-any-context"> style="fixed-case">PlGF style="fixed-case">mRNA expression, resulting in reduced style="fixed-case">PlGF secretion by the trophoblast in response to stress. Therefore, these results further support the targeting of placental style="fixed-case">ER stress as a potential new therapeutic intervention for these pregnancy complications. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.