Interplay between Vascular Endothelial Growth Factor (VEGF) and Nuclear Factor Erythroid 2-related Factor-2 (Nrf2)

Kweider, Nisreen; Fragoulis, Athanassios; Rosén, Christian; Pecks, Ulrich; Rath, Werner; Pufe, Thomas; Wruck, Christoph Jan

doi:10.1074/jbc.m111.286880

Cited by 87 publications

(70 citation statements)

References 46 publications

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“…This directive applies especially to VEGF supplementation in the gravid female because of a myriad of adverse fetal effects from VEGF overexposure that have been observed in animal models 81, 82, 83, 84, 85, 86. Previous studies using free VEGF‐A isoforms, including VEGF‐A 165 87, 88, 89 and VEGF‐A 121 ,36, 64, 90, 91 have demonstrated therapeutic efficacy in treating the maternal syndrome of preeclampsia. In these previous studies, VEGF was administered in vitro,88 by chronic infusion,36, 64 or via adenoviral vector overexpression 31, 87, 89, 90, 91.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies using free VEGF‐A isoforms, including VEGF‐A 165 87, 88, 89 and VEGF‐A 121 ,36, 64, 90, 91 have demonstrated therapeutic efficacy in treating the maternal syndrome of preeclampsia. In these previous studies, VEGF was administered in vitro,88 by chronic infusion,36, 64 or via adenoviral vector overexpression 31, 87, 89, 90, 91. However, David et al raise the concern that adenoviral delivery of VEGF to the mother may risk harming the fetus by breeching the placental barrier 89.…”

Section: Discussionmentioning

confidence: 99%

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A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

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Mahdi

Chapman

et al. 2017

JAHA

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BackgroundPreeclampsia is a hypertensive syndrome that complicates 3% to 5% of pregnancies in the United States. Preeclampsia originates from an improperly vascularized and ischemic placenta that releases factors that drive systemic pathophysiology. One of these factors, soluble fms‐like tyrosine kinase‐1, is believed to sequester vascular endothelial growth factor (VEGF), leading to systemic endothelial dysfunction and hypertension. With the goal of targeting soluble fms‐like tyrosine kinase‐1 while simultaneously preventing fetal exposure to VEGF, we fused VEGF to elastin‐like polypeptide, a biopolymer carrier that does not cross the placental barrier (ELP‐VEGF).Methods and Results ELP‐VEGF restored in vitro endothelial cell tube formation in the presence of plasma from placental ischemic rats. Long‐term administered ELP‐VEGF in pregnant rats accumulated in maternal kidneys, aorta, liver, and placenta, but the protein was undetectable in the pups when administered at therapeutic doses in dams. Long‐term administration of ELP‐VEGF in a placental ischemia rat model achieved dose‐dependent attenuation of hypertension, with blood pressure equal to sham controls at a dose of 5 mg/kg per day. ELP‐VEGF infusion increased total plasma soluble fms‐like tyrosine kinase‐1 levels but dramatically reduced free plasma soluble fms‐like tyrosine kinase‐1 and induced urinary excretion of nitrate/nitrite, indicating enhanced renal nitric oxide signaling. ELP‐VEGF at up to 5 mg/kg per day had no deleterious effect on maternal or fetal body weight. However, dose‐dependent adverse events were observed, including ascites production and neovascular tissue encapsulation around the minipump.Conclusions ELP‐VEGF has the potential to treat the preeclampsia maternal syndrome, but careful dosing and optimization of the delivery route are necessary.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

Logue

Mahdi

Chapman

et al. 2017

JAHA

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“…Conversely, VEGF activates HO-1 via activation of Nrf2 (40). Since both CO and NO, produced from HO-1 and eNOS, respectively, share similar biological properties, such as the ability to regulate angiogenesis and vasodilation, it is now evident that both gaseous molecules do not always work independently, but rather can cross-modulate each other's biological activity in the vasculature.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis via Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

Kim

Lee

et al. 2014

Antioxidants & Redox Signaling

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Aims: Hypoxia induces expression of various genes and microRNAs (miRs) that regulate angiogenesis and vascular function. In this study, we investigated a new functional role of new hypoxia-responsive miR-101 in angiogenesis and its underlying mechanism for regulating heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) expression. Results: We found that hypoxia induced miR-101, which binds to the 3¢untranslated region of cullin 3 (Cul3) and stabilizes nuclear factor erythroid-derived 2-related factor 2 (Nrf2) via inhibition of the proteasomal degradation pathway. miR-101 overexpression promoted Nrf2 nuclear accumulation, which was accompanied with increases in HO-1 induction, VEGF expression, and endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production. The elevated NO-induced S-nitrosylation of Kelch-like ECH-associated protein 1 and subsequent induction of Nrf2-dependent HO-1 lead to further elevation of VEGF production via a positive feedback loop between the Nrf2/HO-1 and VEGF/eNOS axes. Moreover, miR-101 promoted angiogenic signals and angiogenesis both in vitro and in vivo, and these events were attenuated by inhibiting the biological activity of HO-1, VEGF, or eNOS. Moreover, these effects were also observed in aortic rings from HO-1 +/ -and eNOS -/ -mice. Local overexpression of miR-101 improved therapeutic angiogenesis and perfusion recovery in the ischemic mouse hindlimb, whereas antagomiR-101 diminished regional blood flow. Innovation: Hypoxia-responsive miR-101 stimulates angiogenesis by activating the HO-1/VEGF/eNOS axis via Cul3 targeting. Thus, miR-101 is a novel angiomir. Conclusion: Our results provide new mechanistic insights into a functional role of miR-101 as a potential therapeutic target in angiogenesis and vascular remodeling. Antioxid. Redox Signal. 21, 2469-2482.

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“…24 Previous studies have shown that Nrf2 activity is decreased in preeclamptic placenta and its activation might be useful to reduce oxidative stress in tissues. 7,31 Both sFlt-1 and sEng are antiangiogenic factors that have been shown to cause endothelial dysfunction in preeclampsia. Cudmore et al 8 demonstrated that induction of HO-1 by adenovirus transfection or treatment with statins could reduce sFlt-1 and sEng production.…”

Section: Discussionmentioning

confidence: 99%

Sofalcone Upregulates the Nuclear Factor (Erythroid-Derived 2)–Like 2/Heme Oxygenase-1 Pathway, Reduces Soluble fms–Like Tyrosine Kinase-1, and Quenches Endothelial Dysfunction

et al. 2015

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P reeclampsia is a pregnancy specific condition affecting ≈5% to 8% of all pregnancy in women and a leading cause of maternal and perinatal morbidity and mortality.1 An imbalance between angiogenic and antiangiogenic factors leading to endothelial dysfunction is proposed to be a key mechanism of preeclampsia. Previous landmark studies identified that antiangiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), play crucial roles in the development of preeclampsia.2,3 Administration of both sFlt-1 and sEng causes severe preeclamptic phenotype in rodents. Furthermore, sFlt-1 and sEng have also been shown to have predictive significance in clinic in women who go onto to develop preeclampsia. 4Heme oxygenase-1 (HO-1) is an inducible rate-limiting enzyme, which catalyzes free heme into carbon monoxide, free iron, and biliverdin. It is known that HO-1-derived carbon monoxide and biliverdin have strong anti-inflammatory and antioxidant properties.5 Transcription of HO-1 mRNA is Abstract-Preeclampsia is a severe complication of pregnancy, characterized by hypertension, oxidative stress, and severe endothelial dysfunction. Antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin, play key pathophysiological roles in preeclampsia. Heme oxygenase-1 (HO-1) is a cytoprotective, antioxidant enzyme reported to be downregulated in preeclampsia. Studies propose that inducing HO-1 may also decrease sFlt-1 production. Sofalcone, a gastric antiulcer agent in clinical use, is known to induce HO-1 in gastric epithelium. We aimed to investigate whether sofalcone induces HO-1 and reduces sFlt-1 release from primary human placental and endothelial cells and blocks endothelial dysfunction in vitro. We isolated human trophoblasts and endothelial cells (human umbilical vein endothelial cells) and also used uterine microvascular cells. We investigated the effects of sofalcone on (1) HO-1 production, (2) activation of the nuclear factor (erythroid-derived 2)-like 2 pathway, (3) sFlt-1 and soluble endoglin release, (4) tumor necrosis factor α-induced monocyte adhesion and vascular cell adhesion molecule upregulation, and (5) endothelial tubule formation. Sofalcone potently increased HO-1 mRNA and protein in both primary trophoblasts and human umbilical vein endothelial cells. Furthermore, sofalcone treatment caused nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and transactivation of other nuclear factor (erythroid-derived 2)-like 2 responsive genes (NQO1, TXN, and GCLC). Importantly, sofalcone significantly decreased the secretion of sFlt-1 from primary human trophoblasts. Sofalcone potently suppressed endothelial dysfunction in 2 in vitro models, blocking tumor necrosis factor α-induced monocyte adhesion and vascular cell adhesion molecule 1 expression in human umbilical vein endothelial cells. These results indicate that in primary human tissues, sofalcone can potently activate antioxidant nuclear factor (erythroid-derived 2)-like 2/HO-1 pathw...

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Interplay between Vascular Endothelial Growth Factor (VEGF) and Nuclear Factor Erythroid 2-related Factor-2 (Nrf2)

Cited by 87 publications

References 46 publications

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis via Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

Sofalcone Upregulates the Nuclear Factor (Erythroid-Derived 2)–Like 2/Heme Oxygenase-1 Pathway, Reduces Soluble fms–Like Tyrosine Kinase-1, and Quenches Endothelial Dysfunction

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