Metal Transcription Factor-1 Is Involved in Hypoxia-Dependent Regulation of Placenta Growth Factor in Trophoblast-Derived Cells

Nishimoto, Fumihito; Sakata, Masahiro; Minekawa, Ryoko; Okamoto, Yoko; Miyake, A.; Isobe, Aki; Yamamoto, Takatsugu; Takeda, Takashi; Ishida, Emi; Sawada, Kenjiro; Morishige, Kenichiro; Kimura, Tadashi

doi:10.1210/en.2008-0949

Cited by 27 publications

(30 citation statements)

References 44 publications

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“…MTF-1 is activated in cultured sheep pulmonary artery endothelial cells following treatment with a NO donor[31]. Interestingly, MTF-1 expression is decreased under hypoxic conditions in trophoblast and has been implicated in the hypoxic regulation of PGF[32]. The potential effects of NO modulation on MTF-1 expression and/or function in trophoblast are unknown.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide generation affects pro- and anti-angiogenic growth factor expression in primary human trophoblast

et al. 2011

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Objectives Preeclampsia is associated with reduced trophoblast placenta growth factor (PGF) expression, elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased bioactivity of nitric oxide (NO). Elevated sFlt-1 reduces bioavailability of PGF and vascular endothelial growth factor (VEGF) leading to maternal endothelial dysfunction. Although NO can regulate gene expression, its ability to regulate trophoblast expression of angiogenic growth factors is not known. Study Design Human primary term trophoblast and JEG-3 choriocarcinoma cells were cultured under 21%O2 or 1%O2 conditions in the presence or absence of NO donor (SNP) or inhibitor (L-NAME). Effects on PGF, VEGF and Flt-1 isoform mRNA expression were determined by quantitative real time PCR. Changes in expression of soluble protein isoforms of FLT-1 was monitored by ELISA. Results Hypoxia decreased PGF mRNA but increased VEGF, sFlt-1 and Flt-1 mRNA expression in the trophoblast. Generation of NO in trophoblast under 1%O2 culture conditions significantly reversed sFlt-1 mRNA and protein expression, independent of mFlt-1. Conversely NO generation in hypoxic trophoblast increased VEGF and PGF mRNA expression. Conclusions NO production in primary human trophoblast cultures had divergent effects on pro-angiogenic (PGF, VEGF) versus anti-angiogenic (sFlt-1) mRNA expression, resulting in an enhanced pro-angiogenic gene expression environment in-vitro.

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Section: Discussionmentioning

confidence: 99%

Nitric oxide generation affects pro- and anti-angiogenic growth factor expression in primary human trophoblast

et al. 2011

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“…Recently, we have shown that PlGF transcriptional activity is mediated in part by glial cell missing-1 (GCM1) transcription factor in trophoblast [27]. Similarly, metal transcription factor-1 (MTF1) has re cently been shown to regulate PlGF expression in trophoblast [42]. Both of these transcription factors are decreased in hypoxic trophoblast in vitro and in preeclamptic trophoblast in vivo [27;42;43].…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Human PlGF Gene Expression in Trophoblast and Nontrophoblast Cells by Oxygen Tension

et al. 2009

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Objective-To determine the mechanism for differential effects of low oxygen tension on human PlGF gene transcription in trophoblast and nontrophoblast cells.Study Design-Human PlGF reporter clones and real time RT-PCR were used to compare the effects of hypoxia on gene transcription in human trophoblast and nontrophoblast cell lines. Overexpression of HIF-1α, inhibition of HIF-1 function and biochemical assessments of HIF-1 cofactor interactions were used to characterize hypoxia response mechanisms regulating PlGF transcription.Results-PlGF transcription is specifically inhibited by low oxygen tension in trophoblast but is induced in some nontrophoblast cells. Overexpression of HIF-1α in normoxic cells or inhibition of HIF-1 function in hypoxic cells did not significantly alter transcription patterns of the PlGF gene in either cell type.Conclusions-These results suggest that transcriptional repression of PlGF gene expression occurs in human trophoblast exposed to low oxygen tension but that PlGF transcription is stimulated in certain hypoxic nontrophoblast cells. However, regulation of PlGF transcription is not mediated by functional HIF-1 activity in either cell types.

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“…TGF-b3 also promotes the production of sEng (Mano et al 2011). In addition, VEGF and PlGF are induced under hypoxic conditions (Tissot van Patot et al 2004;Nishimoto et al 2009) and are inhibited by sFlt-1. Interestingly, sEng and sFlt-1 expression are both stimulated under ischemic conditions, thus contributing to the systemic endothelial dysfunction (Gilbert et al 2007(Gilbert et al , 2009).…”

Section: Mechanisms Of Placentation Defects In Preeclampsiamentioning

confidence: 99%

Molecular mechanisms of preeclampsia

Mutter

Karumanchi

2008

Microvascular Research

259

181

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Preeclampsia is a pregnancy-specific disease characterized by new onset hypertension and proteinuria after 20 wk of gestation. It is a leading cause of maternal and fetal morbidity and mortality worldwide. Exciting discoveries in the last decade have contributed to a better understanding of the molecular basis of this disease. Epidemiological, experimental, and therapeutic studies from several laboratories have provided compelling evidence that an antiangiogenic state owing to alterations in circulating angiogenic factors leads to preeclampsia. In this review, we highlight the role of key circulating antiangiogenic factors as pathogenic biomarkers and in the development of novel therapies for preeclampsia.

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Metal Transcription Factor-1 Is Involved in Hypoxia-Dependent Regulation of Placenta Growth Factor in Trophoblast-Derived Cells

Cited by 27 publications

References 44 publications

Nitric oxide generation affects pro- and anti-angiogenic growth factor expression in primary human trophoblast

Nitric oxide generation affects pro- and anti-angiogenic growth factor expression in primary human trophoblast

Differential Regulation of Human PlGF Gene Expression in Trophoblast and Nontrophoblast Cells by Oxygen Tension

Molecular mechanisms of preeclampsia

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