NF-κB contributes to transcription of placenta growth factor and interacts with metal responsive transcription factor-1 in hypoxic human cells

Cramer, Mirjam; Nagy, Ivana; Murphy, Brian J.; Gassmann, Max; Hottiger, Michael O.; Georgiev, Oleg; Schaffner, Walter

doi:10.1515/bc.2005.101

Cited by 78 publications

(53 citation statements)

References 40 publications

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“…Despite the several reports stating that the expression of PlGF is upregulated in vitro under hypoxic condition in endothelial cells [28, 29], fibroblasts [35], cardiomyocytes [27] and in cancer cell lines [36, 37], only occasional data are available on visualization of PlGF in vivo in tissues in which pathological angiogenesis or wound healing, and consequently hypoxia, occurs. This was due to absence of efficient anti-PlGF antibodies for IHC analyses.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia activates placental growth factor expression in lymphatic endothelial cells

et al. 2017

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Placental growth factor (PlGF), a proangiogenic member of vascular endothelial growth family, is active during pathological conditions like cancer, metastasis formation and hind limb ischemia and in wound healing. Endothelial cells express PlGF and hypoxia positively modulates in vitro its expression. To verify whether hypoxia modulates PlGF expression in different cellular contexts and in vivo, we first analyzed five human and five mouse cancer cell lines showing that in eight of them hypoxia positively modulates PlGF. Next, we analyzed xenograft colorectal cancer tumors showing that human cancer cells were able to express PlGF in hypoxic area of the tumor. Surprisingly, we did not visualize mouse PlGF in CD31 positive tumor vessels, but in low CD31 positive vessels, a characteristic of lymphatic vessels. We found that hypoxia effectively activates PlGF expression in lymphatic endothelial cells as well as in LYVE1 positive tumor vessels. We also investigated two additional mouse angiogenic models, hind limb ischemia and wound healing, and we confirmed that lymphatic vessels of both ischemic muscles and skin express PlGF. These results show for the first time that hypoxia activates PlGF expression in lymphatic endothelial cells, which have to be considered an additional source for PlGF production in pathological contexts.

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Section: Discussionmentioning

confidence: 99%

Hypoxia activates placental growth factor expression in lymphatic endothelial cells

et al. 2017

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“…It has been shown that Ang II could stimulate the expression of hypoxia inducible factor-1α (HIF-1α) [43], and HIF-1α seems to be involved in the enhanced PlGF expression stimulated by hypoxia [19]. The hypoxia-inducible PlGF expression is mediated through NF-κB, metal-regulatory transcription factor-1(MTF-1) and the interaction between them [19].…”

Section: Discussionmentioning

confidence: 99%

“…The PlGF expression can be induced by hypoxia and various pro-inflammatory stimuli [18]. This induction is mediated via NF-kappa B and metal response transcription factor-1(MTF-1)[19]. However, the regulation of PlGF expression in vascular cells, and its mechanisms of action have received little attention in atherosclerosis research.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II upregulates the expression of placental growth factor in human vascular endothelial cells and smooth muscle cells

Pan

Zhang

et al. 2010

BMC Cell Biol

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BackgroundAtherosclerosis is now recognized as a chronic inflammatory disease. Angiotensin II (Ang II) is a critical factor in inflammatory responses, which promotes the pathogenesis of atherosclerosis. Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family cytokines and is associated with inflammatory progress of atherosclerosis. However, the potential link between PlGF and Ang II has not been investigated. In the current study, whether Ang II could regulate PlGF expression, and the effect of PlGF on cell proliferation, was investigated in human vascular endothelial cells (VECs) and smooth muscle cells (VSMCs).ResultsIn growth-arrested human VECs and VSMCs, Ang II induced PlGF mRNA expression after 4 hour treatment, and peaked at 24 hours. 10-6 mol/L Ang II increased PlGF protein production after 8 hour treatment, and peaked at 24 hours. Stimulation with Ang II also induced mRNA expression of VEGF receptor-1 and -2(VEGFR-1 and -2) in these cells. The Ang II type I receptor (AT1R) antagonist blocked Ang II-induced PlGF gene expression and protein production. Several intracellular signals elicited by Ang II were involved in PlGF synthesis, including activation of protein kinase C, extracellular signal-regulated kinase 1/2 (ERK1/2) and PI3-kinase. A neutralizing antibody against PlGF partially inhibited the Ang II-induced proliferation of VECs and VSMCs. However, this antibody showed little effect on the basal proliferation in these cells, whereas blocking antibody of VEGF could suppress both basal and Ang II-induced proliferation in VECs and VSMCs.ConclusionOur results showed for the first time that Ang II could induce the gene expression and protein production of PlGF in VECs and VSMCs, which might play an important role in the pathogenesis of vascular inflammation and atherosclerosis.

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“…led to more increased PlGF levels. However, a relationship between MTF-1 and NF-B p65 in the hypoxic induction of PlGF transcription was not definitively observed (51).…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2008

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Placenta growth factor (PlGF) is a placental angiogenic factor. Metal-responsive transcription factor (MTF)-1 was reported to take part in the hypoxic induction of PlGF in RAS-transformed mouse fibroblasts. We contrarily showed that PlGF mRNA and protein levels decreased under hypoxia in a choriocarcinoma BeWo cell line derived from trophoblast. In this report, we examined whether hypoxia-dependent regulation of the PlGF gene in these cells also depends on MTF-1. We analyzed the effect of hypoxia on MTF-1 expression, and it was revealed to be decreased. Moreover, MTF-1 small interfering RNA treatment decreased PlGF mRNA level. To investigate the transcription of PlGF under hypoxia, we cloned promoter region of the human PlGF. Promoter deletion analysis suggested that triple repeats of metal-responsive element located between -511 and -468 bp in the promoter are important for the hypoxic regulation of PlGF. Treatment with MTF-1 small interfering RNA resulted in the significant decreased luciferase activity in PlGF reporter constructs. Chromatin immunoprecipitation showed the binding of the MTF-1 protein to the promoter region. We examined MTF-1 immunoreactivity in trophoblasts of term placental tissue from patients with normal pregnancies and preeclampsia, which represents a condition of placental hypoxia. Immunoreactivity of the MTF-1 protein was decreased in placentas from pregnant women with preeclampsia when compared with those from normal pregnant women. Taken together, these findings suggest that MTF-1 is involved in hypoxia-dependent regulation of PlGF in trophoblast-derived cells.

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NF-κB contributes to transcription of placenta growth factor and interacts with metal responsive transcription factor-1 in hypoxic human cells

Cited by 78 publications

References 40 publications

Hypoxia activates placental growth factor expression in lymphatic endothelial cells

Hypoxia activates placental growth factor expression in lymphatic endothelial cells

Angiotensin II upregulates the expression of placental growth factor in human vascular endothelial cells and smooth muscle cells

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

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