scholarly journals Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1452
Author(s):  
Maria Grazia Rossino ◽  
Matteo Lulli ◽  
Rosario Amato ◽  
Maurizio Cammalleri ◽  
Massimo Dal Monte ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Retinopathy ◽  
Ex Vivo ◽  
Hypoxia Inducible Factor ◽  
Related Factor ◽  
Vegf Receptor ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Autocrine Loop ◽  
Retinal Explants

Background: Oxidative stress (OS) plays a central role in diabetic retinopathy (DR), triggering expression and release of vascular endothelial growth factor (VEGF), the increase of which leads to deleterious vascular changes. We tested the hypothesis that OS-stimulated VEGF induces its own expression with an autocrine mechanism. Methods: MIO-M1 cells and ex vivo mouse retinal explants were treated with OS, with exogenous VEGF or with conditioned media (CM) from OS-stressed cultures. Results: Both in MIO-M1 cells and in retinal explants, OS or exogenous VEGF induced a significant increase of VEGF mRNA, which was abolished by VEGF receptor 2 (VEGFR-2) inhibition. OS also caused VEGF release. In MIO-M1 cells, CM induced VEGF expression, which was abolished by a VEGFR-2 inhibitor. Moreover, the OS-induced increase of VEGF mRNA was abolished by a nuclear factor erythroid 2-related factor 2 (Nrf2) blocker, while the effect of exo-VEGF resulted Nrf2-independent. Finally, both the exo-VEGF- and the OS-induced increase of VEGF expression were blocked by a hypoxia-inducible factor-1 inhibitor. Conclusions: These results are consistent with the existence of a retinal VEGF autocrine loop triggered by OS. This mechanism may significantly contribute to the maintenance of elevated VEGF levels and therefore it may be of central importance for the onset and development of DR.

scholarly journals Induction of Redox-Active Gene Expression by CoCl2 Ameliorates Oxidative Stress-Mediated Injury of Murine Auditory Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 399 ◽  
Author(s):  
Jhang Ho Pak ◽  
Junyeong Yi ◽  
Sujin Ryu ◽  
In Ki Kim ◽  
Jung-Woong Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ganglion Cells ◽  
Stria Vascularis ◽  
Hypoxia Inducible Factor ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Luciferase Reporter ◽  
Related Factor ◽  
Redox Active

Free radicals formed in the inner ear in response to high-intensity noise, are regarded as detrimental factors for noise-induced hearing loss (NIHL). We reported previously that intraperitoneal injection of cobalt chloride attenuated the loss of sensory hair cells and NIHL in mice. The present study was designed to understand the preconditioning effect of CoCl2 on oxidative stress-mediated cytotoxicity. Treatment of auditory cells with CoCl2 promoted cell proliferation, with increases in the expressions of two redox-active transcription factors (hypoxia-inducible factor 1α, HIF-1α, nuclear factor erythroid 2-related factor 2; Nrf-2) and an antioxidant enzyme (peroxiredoxin 6, Prdx6). Hydrogen peroxide treatment resulted in the induction of cell death and reduction of these protein expressions, reversed by pretreatment with CoCl2. Knockdown of HIF-1α or Nrf-2 attenuated the preconditioning effect of CoCl2. Luciferase reporter analysis with a Prdx6 promoter revealed transactivation of Prdx6 expression by HIF-1α and Nrf-2. The intense immunoreactivities of HIF-1α, Nrf-2, and Prdx6 in the organ of Corti (OC), spiral ganglion cells (SGC), and stria vascularis (SV) of the cochlea in CoCl2-injected mice suggested CoCl2-induced activation of HIF-1α, Nrf-2, and Prdx6 in vivo. Therefore, we revealed that the protective effect of CoCl2 is achieved through distinctive signaling mechanisms involving HIF-1α, Nrf-2, and Prdx6.

MicroRNA-199a Protects Diabetic Retinopathy Under Streptozotocin Conditions by Vascular Endothelial Growth Factor (VEGF)

2020 ◽  
Vol 10 (3) ◽  
pp. 408-412
Author(s):  
Xuemei Wu ◽  
Liang Hui
Keyword(s):  
Oxidative Stress ◽  
Diabetic Retinopathy ◽  
Cell Damage ◽  
Vascular Endothelial ◽  
Rt Pcr ◽  
Vegf Expression ◽  
Inflammatory Stress ◽  
Over Expression ◽  
Vegf Signaling ◽  
Endothelial Growth Factor

Inflammatory stress and angiogenesis participate in diabetic retinopathy. miR-199α could inhibit the elevation of wound angiogenesis by suppressing TNF-α and NF-κB pathway. The mechanism of miR-199a in streptozotocin (STZ)-induced cell damage was assessed by ELLISA kit, western blotting, real-time RT-PCR. Reactive oxygen Species (ROS) was measured by flow cytometry. The over expression of miR-199a decreased the STZ-stimulated oxidative stress, inflammatory response, as well as VEGF expression. In conclusion, our results validated that overexpression of miR-199a protects RMECs from STZ-induced inflammation, oxidative stress and angiogenesis by targeting, at least partly, the VEGF signaling.

scholarly journals Differential Regulation of Tumor Angiogenesis by Distinct ErbB Homo- and Heterodimers

2002 ◽  
Vol 13 (11) ◽  
pp. 4029-4044 ◽  
Author(s):  
Lily Yen ◽  
Naciba Benlimame ◽  
Zeng-Rong Nie ◽  
Dingzhang Xiao ◽  
Taiqi Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mutational Analysis ◽  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Extracellular Signal ◽  
Erbb Receptor Family

Interactions between cancer cells and their microenvironment are critical for the development and progression of solid tumors. This study is the first to examine the role of all members of the ErbB tyrosine kinase receptors (epidermal growth factor receptor [EGFR], ErbB-2, ErbB-3, or ErbB-4), expressed singly or as paired receptor combinations, in the regulation of angiogenesis both in vitro and in vivo. Comparison of all receptor combinations reveals that EGFR/ErbB-2 and ErbB-2/ErbB-3 heterodimers are the most potent inducers of vascular endothelial growth factor (VEGF) mRNA expression compared with EGFR/ErbB-3, EGFR/ErbB-4, ErbB-2/ErbB-4, and ErbB-3/ErbB-4. Immunohistochemistry of tumor xenografts overexpressing these heterodimers shows increased VEGF expression and remarkably enhanced vascularity. Enhanced VEGF expression is associated with increased VEGF transcription. Deletional analysis reveals that ErbB-mediated transcriptional up-regulation of VEGF involves a hypoxia-inducible factor 1-independent responsive region located between nucleotides −88 to −66 of the VEGF promoter. Mutational analysis reveals that the Sp-1 and AP-2 transcription factor binding elements within this region are required for up-regulation of VEGF by heregulin β1 and that this up-regulation is dependent on the activity of extracellular signal-related protein kinases. These results emphasize the biological implications of cell signaling diversity among members of the ErbB receptor family in regulation of the tumor microenvironment.

scholarly journals Stathmin, a Microtubule Regulatory Protein, Is Associated with Hypoxia-Inducible Factor-1α Levels in Human Endometrial and Endothelial Cells

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2413-2418 ◽  
Author(s):  
Mikihiro Yoshie ◽  
Eri Miyajima ◽  
Satoru Kyo ◽  
Kazuhiro Tamura
Keyword(s):  
Endothelial Cells ◽  
Menstrual Cycle ◽  
Regulatory Protein ◽  
Hypoxia Inducible Factor ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Endometrial Cells ◽  
Protein Levels

Local hypoxia that occurs during menstruation triggers angiogenesis that is crucial for cyclical remodeling of the endometrium during the menstrual cycle. Hypoxia is thought to be important for the expression of vascular endothelial growth factor (VEGF) via its transcriptional factor, hypoxia inducible factor (HIF)-1α, in the endometrium. The activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway may modulate HIF-1α protein levels. Stathmin, a microtubule regulatory protein, was expressed in the stroma, glandular epithelium, and vascular endothelium in human endometrium. In this study, we examined a possible role of stathmin in hypoxia-induced HIF-1α and VEGF expression in primary isolated and immortalized human endometrial stromal cells, glandular epithelial cells, and human umbilical venous endothelial cells (HUVEC). Knocking down stathmin expression using small interfering RNA caused microtubule stabilization and inhibited hypoxia-induced VEGF mRNA expression via the reduction of HIF-1α protein levels in endometrial cells and HUVEC. Treatment of the cells with a PI3K inhibitor, wortmannin, inhibited the expression of VEGF mRNA and the accumulation of HIF-1α protein. Silencing of stathmin expression repressed the activation (phosphorylation) of Akt in endometrial cells and HUVEC. These results suggest that endometrial stathmin is linked to HIF-1α protein accumulation and VEGF expression through the PI3K/Akt signaling pathway and may be involved in regeneration of the endometrium during the menstrual cycle in human uterine cells.

Effect of stimulation frequency on angiogenesis and gene expression in ischemic skeletal muscle of rabbit

2009 ◽  
Vol 87 (5) ◽  
pp. 396-401 ◽  
Author(s):  
Mei Shen ◽  
Jing Gao ◽  
Jianan Li ◽  
Juan Su
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Fetal Liver ◽  
Hypoxia Inducible Factor ◽  
Capillary Density ◽  
Control Group ◽  
Vegf Receptor ◽  
Vegf Mrna ◽  
Artery Ligation ◽  
40 Hz

To examine the comparative effects of different frequencies of electrical stimulation (ES) on angiogenesis and gene expression, New Zealand white rabbits with femoral artery ligation in one hindlimb and electrode implantation on the sciatic nerve of the same hindlimb were randomly assigned to 4 groups: control group, 1 Hz group, 10 Hz group, and 40 Hz group. The ES procedure involved 5 min stimulation, followed by 5 min rest, repeated 8 times daily for 4 consecutive weeks. The resting blood flow (RBF) was measured via the microspheres technique. Collateralization was evaluated by immunohistochemistry. Angiogenic factors were analyzed by real-time RT-PCR. Both RBF and capillary density were significantly increased in the 10 Hz and 40 Hz groups, but were not changed in the 1 Hz group. Vascular endothelial growth factor (VEGF) mRNA was highest in the 40 Hz group. Hypoxia-inducible factor 1α (HIF-1α) mRNA was significantly elevated only in the 40 Hz group. VEGF receptor fetal liver kinase 1 (Flk-1) mRNA was upregulated equally in the 10 Hz and 40 Hz groups, but fibroblast growth factor 2 (FGF-2) mRNA did not change in any group. Our results suggest that the optimal frequency of ES for angiogenesis is within the 10–40 Hz range.

Hypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel therapeutic targets

2011 ◽  
Vol 300 (2) ◽  
pp. C226-C231 ◽  
Author(s):  
Toshio Miyata ◽  
Shunya Takizawa ◽  
Charles van Ypersele de Strihou
Keyword(s):  
Oxidative Stress ◽  
Defense Mechanisms ◽  
Tissue Injury ◽  
Hypoxia Inducible Factor ◽  
Oxygen Metabolism ◽  
Related Factor ◽  
Novel Therapy ◽  
Prolyl Hydroxylases ◽  
Hypoxic Tolerance ◽  
And Oxidative Stress

A variety of human disorders, e.g., ischemic heart disease, stroke, kidney disease, eventually share the deleterious consequences of a common, hypoxic and oxidative stress pathway. In this review, we utilize recent information on the cellular defense mechanisms against hypoxia and oxidative stress with the hope to propose new therapeutic tools. The hypoxia-inducible factor (HIF) is a key player as it activates a broad range of genes protecting cells against hypoxia. Its level is determined by its degradation rate by intracellular oxygen sensors prolyl hydroxylases (PHDs). There are three different PHD isoforms (PHD1–3). Small molecule PHD inhibitors improve hypoxic injury in experimental animals but, unfortunately, may induce adverse effects associated with PHD2 inhibition, e.g., angiogenesis. As yet, no inhibitor specific for a distinct PHD isoform is currently available. Still, the specific disruption of the PHD1 gene is known to induce hypoxic tolerance, without angiogenesis and erythrocytosis, by reprogramming basal oxygen metabolism with an attendant decreased oxidative stress in hypoxic mitochondria. A specific PHD1 inhibitor might therefore offer a novel therapy against hypoxia. The nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates the basal and inducible expression of numerous antioxidant stress genes. Disruption of its gene exacerbates oxidative tissue injury. Nrf2 activity is modulated by Kelch-like ECH-associated protein 1 (Keap1), an intracellular sensor for oxidative stress. Inhibitors of Keap 1 may prove therapeutic against oxidative tissue injury.

scholarly journals Electroacupuncture on ST36 and GB39 Acupoints Inhibits Synovial Angiogenesis via Downregulating HIF-1α/VEGF Expression in a Rat Model of Adjuvant Arthritis

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Jun Zhu ◽  
Chengguo Su ◽  
Yuzhou Chen ◽  
Xinyu Hao ◽  
Jianzhen Jiang
Keyword(s):  
Synovial Tissue ◽  
Rat Model ◽  
Adjuvant Arthritis ◽  
Hypoxia Inducible Factor ◽  
Sprague Dawley ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Real Time Quantitative Pcr ◽  
Protein Levels ◽  
Cd34 Expression

Introduction. The hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) play a key role in synovial angiogenesis in rheumatoid arthritis (RA). Therefore, this study aimed to test the hypothesis that electroacupuncture (EA) may inhibit RA synovial angiogenesis via HIF-1α/VEGF expression. Methods. Sprague-Dawley rats were randomly distributed to 4 groups: control, adjuvant arthritis (AA), AA+electroacupuncture (AA+EA), and AA+sham EA groups. AA model was induced by injection of Freund's complete adjuvant in bilateral hind footpad. 3 days after injection, EA was delivered to the acupoints Zusanli (ST 36) and Xuanzhong (GB 39) once every two days for a total of 8 times in the AA+EA group, while sham EA treatment was applied in the AA+sham EA group. The arthritis score, paw volume, and H&E staining for each animal were measured. CD34 expression in synovial tissue of ankle joint was observed by immunohistochemistry. HIF-1α and VEGF mRNA and protein levels in synovial tissue were determined by real-time quantitative PCR and Western blot, respectively. Results. Compared with rats in AA group, EA stimulation significantly decreased arthritis scores, paw volume, and pathological damage of synovial tissues. Moreover, EA markedly suppressed the synovial angiogenesis of AA rats, as evidenced by reduced CD34 positive expression. Furthermore, EA significantly reduced HIF-1α and VEGF mRNA and protein levels in synovial of AA rats. Finally, the CD34 expression in synovial tissue was positively correlated with HIF-1α and VEGF protein levels. Conclusion. EA on ST36 and GB39 acupoints can effectively inhibit synovial angiogenesis in the AA rat model via downregulating HIF-1α/VEGF expression.

scholarly journals Acute iodine deficiency induces a transient VEGF-dependent microvascular response in mammary glands involving HIF-1, ROS, and mTOR

2018 ◽  
Vol 315 (4) ◽  
pp. C544-C557 ◽  
Author(s):  
Jessica Vanderstraeten ◽  
Hanane Derradji ◽  
Pierre Sonveaux ◽  
Ides M. Colin ◽  
Marie-Christine Many ◽  
...  
Keyword(s):  
Iodine Deficiency ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Transient Increase ◽  
Vegf Receptor ◽  
Mcf7 Cells ◽  
Vegf Mrna ◽  
Deficient Diet

Iodine deficiency (ID), which affects almost two billion people worldwide, is associated with breast pathologies such as fibrosis in human and induces breast atypia in animal models. Because ID induces vascular activation in the thyroid, another iodide-uptaking organ, and as breast is also sensitive to ID, we aimed to characterize ID-induced effects on the breast microvasculature in vivo and in two different breast cell lines in vitro. Virgin and lactating NMRI mice received an iodide-deficient diet and a Na+/I− symporter inhibitor for 1 to 20 days. Some virgin mice were treated with vascular endothelial growth factor A (VEGF) or VEGF receptor inhibitors. In vitro, ID was induced in MCF7 and MCF12A cells by replacing the iodide-containing medium by an iodide-deficient medium. In vivo, VEGF expression was increased following ID in mammary tissues. Consequently, ID induced a transient increase in mammary gland blood flow, measured after anesthesia, in virgin and lactating mice, which was repressed by VEGF or VEGF receptor inhibitors. In MCF7 cells, ID induced a transient increase in reactive oxygen species, followed by an increase in hypoxia-inducible factor-1α (HIF-1α) protein and VEGF mRNA expression. Antioxidant N-acetylcysteine and mammalian target of rapamycin (mTOR) inhibitor blocked ID-induced HIF-1α protein increase and VEGF transcription. However, mTOR activity was not inhibited by N-acetylcysteine. Similar responses were observed in MCF12A cells. These data indicate that ID activates the canonical VEGF pathway and mTOR in breast tissues, which provides new insights to better understand the correlation between ID, vascular activation, and breast pathologies.

scholarly journals Sp1 Is Involved in Akt-mediated Induction of VEGF Expression through an HIF-1–independent Mechanism

2004 ◽  
Vol 15 (11) ◽  
pp. 4841-4853 ◽  
Author(s):  
Nabendu Pore ◽  
Shuang Liu ◽  
Hui-Kuo Shu ◽  
Bin Li ◽  
Daphne Haas-Kogan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Proximal Promoter ◽  
Alternative Mechanism ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Activity Increase ◽  
Potent Inducer

Increased expression of vascular endothelial growth factor (VEGF) contributes to the growth of many tumors by increasing angiogenesis. Although hypoxia is a potent inducer of VEGF, we previously showed that epidermal growth factor receptor amplification and loss of PTEN, both of which can increase phosphatidylinositol-3-kinase (PI3K) activity, increase VEGF expression. Using both adenoviral vectors and a cell line permanently expressing constitutively active myristoylated Akt (myrAkt), we show that activation of Akt, which is downstream of PI3K, increases VEGF expression in vitro and increases angiogenesis in a Matrigel plug assay. Transient transfection experiments using reporter constructs containing the VEGF promoter showed that up-regulation of VEGF by Akt is mediated through Sp1 binding sites located in the proximal promoter. Small interfering RNA directed against Sp1 prevented the induction of VEGF mRNA in response to myrAkt but not to hypoxia. Expression of myrAkt is associated with increased phosphorylation of Sp1 and its increased binding to a probe corresponding to the -88/-66 promoter region. In conclusion, our results indicate that Sp1 is required for transactivation of the VEGF by Akt. Others have proposed that the PI3K/Akt pathway can increase VEGF expression via the hypoxia-inducible factor 1 (HIF-1); however, our results suggest an alternative mechanism can also operate.

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