Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy
"> Figure 1
<p>(<b>A</b>) and (<b>B</b>) represent vascular endothelial growth factor (<span class="html-italic">VEGF</span>) mRNA expression in MIO-M1 cells and in retinal explants, respectively, exposed to oxidative stress (OS; 400 µM H<sub>2</sub>O<sub>2</sub> for MIO-M1 cells and 100 µM H<sub>2</sub>O<sub>2</sub> for retinal explants) for 24 h and effect of a vascular endothelial growth factor receptor 2 (VEGFR2) blocker (0.1 µM Apatinib for MIO-M1 cells and 25 µM SU1498 for retinal explants). * <span class="html-italic">p</span> < 0.05 and ** <span class="html-italic">p</span> < 0.01 relative to controls (Ctrl); <sup>§</sup> <span class="html-italic">p</span> < 0.05 and <sup>§§</sup> <span class="html-italic">p</span> < 0.01 relative to OS. (<b>C</b>) and (<b>D</b>) represent <span class="html-italic">VEGF</span> mRNA expression in MIO-M1 cells and in retinal explants, respectively, exposed to different concentrations of exogenous VEGF (exo-VEGF) for 24 h. * <span class="html-italic">p</span> < 0.05 ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001 relative to Ctrl. (<b>E</b>) and (<b>F</b>) represent <span class="html-italic">VEGF</span> mRNA expression in MIO-M1 cells and in retinal explants, respectively, in response to the most effective concentration of exo-VEGF (1 ng/mL in MIO-M1 cells and 10 ng/mL in retinal explants) and the effect of a VEGFR2 blocker (Apatinib for MIO-M1 cells and SU1498 for retinal explants). * <span class="html-italic">p</span> < 0.05 and *** <span class="html-italic">p</span> < 0.001 relative to Ctrl; <sup>§</sup> <span class="html-italic">p</span> < 0.05 and <sup>§§</sup> <span class="html-italic">p</span> < 0.01 relative to exo-VEGF. <span class="html-italic">n</span> = 3 in (<b>A</b>–<b>E</b>); <span class="html-italic">n</span> = 5 in (<b>F</b>).</p> "> Figure 2
<p>VEGFR2 immunofluorescence in MIO-M1 cells (<b>A</b>,<b>C</b>,<b>E</b>) and in cryostat sections of retinal explants (<b>B</b>,<b>D</b>,<b>F</b>) in Ctrl (<b>A</b>,<b>B</b>), in the presence of 1 ng/mL (MIO-M1 cells) or 10 ng/mL (retinal explants) of exo-VEGF (<b>C</b>,<b>D</b>) and in the presence of exo-VEGF with a VEGR2 blocker (0.1 µM Apatinib for MIO-M1 cells and 25 µM SU1498 for retinal explants: <b>E</b>,<b>F</b>). In the images of MIO-M1 cells (<b>A</b>,<b>C</b>,<b>E</b>), above background, specific VEGFR2 immunolabeling was highlighted using Adobe Photoshop, and it appears as bright, whitish dots. Background, non-specific immunostaining is dark green. Cell nuclei were visualized with Hoechst and actin filaments with rhodamine-conjugated phalloidin. In retinal explants (<b>B</b>,<b>D</b>,<b>F</b>), specific VEGR2 immunostaining is bright green, while cell nuclei were visualized with DAPI counterstain. Putative immunolabeled blood vessels are indicated by arrows; putative immunolabeled Müller cell processes are indicated by arrowheads. GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; ONL, outer nuclear layer; OPL, outer plexiform layer. Scale bars, 20 µm. <b>G</b> and <b>H</b> indicate VEGFR2 immunofluorescence levels normalized to Ctrl in MIO-M1 cells and in retinal explants, respectively, in the different experimental conditions. eV, exo-VEGF. * <span class="html-italic">p</span> < 0.05 and ** <span class="html-italic">p</span> < 0.01 relative to Ctrl. <span class="html-italic">n</span> = 4.</p> "> Figure 3
<p>(<b>A</b>) VEGF release in the culture medium of MIO-M1 cells exposed to OS for 24 h, as measured with ELISA. (<b>B</b>) <span class="html-italic">VEGF</span> mRNA expression in MIO-M1 cells incubated for 24 h in the conditioned medium of untreated MIO-M1 cells (CM-Ctrl) or of MIO-M1 cells exposed to OS for 24 h (CM-OS), with or without the VEGFR2 blocker Apatinib at 0.1 µM. *** <span class="html-italic">p</span> < 0.001 relative to control MIO-M1 cell cultures (Ctrl) (<b>A</b>) or to untreated MIO-M1 cell cultures (that is incubated in non-conditioned medium, Unt) (<b>B</b>), <sup>§§§</sup> <span class="html-italic">p</span> < 0.001 relative to CM-OS, and <sup>###</sup> <span class="html-italic">p</span> < 0.001 relative to CM-Ctrl as evaluated with one-way ANOVA followed by Newman–Keuls post-hoc test. <sup>o</sup> <span class="html-italic">p</span> < 0.005 with respect to Unt as evaluated with one-way ANOVA followed by uncorrected Fisher’s LSD post-hoc test. <span class="html-italic">n</span> = 4 in (<b>A</b>); <span class="html-italic">n</span> = 6 in (<b>B</b>). (<b>C</b>–<b>G</b>): Images of VEGFR2 immunofluorescence in MIO-M1 cells in the experimental conditions as in (<b>B</b>). Other details as in <a href="#cells-09-01452-f002" class="html-fig">Figure 2</a>. Scale bar, 20 µm.</p> "> Figure 4
<p>(<b>A</b>) VEGF release in the culture medium of retinal explants exposed to OS for 24 h, as measured with ELISA. (<b>B</b>) <span class="html-italic">VEGF</span> mRNA expression in retinal explants incubated for 24 h in non-conditioned medium (Ctrl) or in explants incubated for 24 h in the conditioned medium of explants exposed to OS for 24 h (CM-24h). (<b>C</b>) VEGF release in the culture medium of retinal explants exposed to OS for 5 days, as measured with ELISA. (<b>D</b>) <span class="html-italic">VEGF</span> mRNA expression in retinal explants incubated for 24 h in the conditioned medium of untreated explants (CM-Ctrl) or in explants incubated for 24 h in the conditioned medium of explants exposed to OS for 5 days (CM-5D). ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001 relative to Ctrl. <span class="html-italic">n</span> = 3 in all graphs.</p> "> Figure 5
<p>Immunofluorescence images documenting nuclear factor erythroid 2-related factor 2 (Nrf2) production and nuclear translocation in Ctrl, OS-treated (OS) and in OS-treated MIO-M1 cells incubated in the presence of the Nrf2 inhibitor ML385 at 5 µM (OS + ML385). (<b>A1</b>), (<b>B1</b>) and (<b>C1</b>) show the overall Nrf2 immunostaining of MIO-M1 cells in the three different conditions; (<b>A2</b>), (<b>B2</b>) and (<b>C2</b>) show the Hoechst-stained cell nuclei; (<b>A3</b>), (<b>B3</b>) and (<b>C3</b>) are merged images of the previous two; (<b>A4</b>), (<b>B4</b>) and (<b>C4</b>) show Nrf2 immunostaining limited to the cell nucleus. Scale bar, 50 µm. The histograms in (<b>D</b>) represent the quantification of immunofluorescence intensity within the nuclei of MIO-M1 cells in the different experimental conditions. The values are relative to that corresponding to 0 µM ML385. ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001 relative to 0 µM ML385; <sup>§§</sup> <span class="html-italic">p</span> < 0.01 relative to OS + 0 µM ML385; <sup>###</sup> <span class="html-italic">p</span> < 0.001 relative to OS + 1 µM ML385. The histograms in (<b>E</b>) represent <span class="html-italic">VEGF</span> mRNA expression in MIO-M1 cells exposed to OS for 24 h and effect of the Nrf2 inhibitor ML385. ** <span class="html-italic">p</span> < 0.01 relative to Ctrl; <sup>§§</sup> <span class="html-italic">p</span> < 0.01 relative to OS. <span class="html-italic">n</span> = 8 in (<b>D</b>); <span class="html-italic">n</span> = 3 in (<b>E</b>).</p> "> Figure 6
<p>Immunofluorescence images documenting Nrf2 production and nuclear translocation in Ctrl, in exo-VEGF-treated and in exo-VEGF-treated MIO-M1 cells incubated in the presence of the Nrf2 inhibitor ML385 (exo-VEGF + ML385). (<b>A1</b>), (<b>B1</b>) and (<b>C1</b>) show the overall Nrf2 immunostaining of MIO-M1 cells in the three different conditions; (<b>A2</b>), (<b>B2</b>) and (<b>C2</b>) show the Hoechst-stained cell nuclei; (<b>A3</b>), (<b>B3</b>) and (<b>C3</b>) are merged images of the previous two; (<b>A4</b>), (<b>B4</b>) and (<b>C4</b>) show Nrf2 immunostaining limited to the cell nucleus. Scale bar, 50 µm. The histograms in (<b>D</b>) represent the quantification of immunofluorescence intensity within the nuclei of MIO-M1 cells in the different experimental conditions. The values are relative to that corresponding to 0 µM ML385; eV, exo-VEGF. The histograms in (<b>E</b>) represent <span class="html-italic">VEGF</span> mRNA expression in MIO-M1 cells exposed to exo-VEGF (eV) for 24 h and effect of the Nrf2 inhibitor ML385. *** <span class="html-italic">p</span> < 0.001 relative to Ctrl. <span class="html-italic">n</span> = 4 in (<b>D</b>); <span class="html-italic">n</span> = 3 in (<b>E</b>).</p> "> Figure 7
<p><span class="html-italic">VEGF</span> mRNA expression in MIO-M1 cells exposed to OS or to exo-VEGF (eV) for 24 h and effect of the hypoxia inducible factor-1 inhibitor acriflavine (ACF) at 5 µM. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001 relative to Ctrl; <sup>§§§</sup> <span class="html-italic">p</span> < 0.001 relative to OS; <sup>###</sup> <span class="html-italic">p</span> < 0.001 relative to eV. <span class="html-italic">n</span> = 4.</p> "> Figure 8
<p>Schematic interpretation of the results of the present study and of other data in the literature showing the possible mechanism of an OS-induced VEGF autocrine loop in the retina. This mechanism can be divided into two parts (pathways). According to our observations, in “pathway 1”, OS triggers Nrf2 activation and nuclear translocation. In the nucleus, Nrf2 induces the expression of antioxidant genes, and in particular the one coding the HO-1 enzyme, which is reported in the literature to be able to stabilize HIF-1α. For the sake of simplicity, the diagram does not indicate HIF-1α or STAT3 nuclear translocation, induction of <span class="html-italic">VEGF</span> transcription, VEGF translation, or VEGF release, but simply indicates that HIF-1α stabilization results in VEGF release. This activates “pathway 2”, in which the released VEGF would bind to VEGFR2, which in turn (likely through STAT3 activation, according to the literature) would again stimulate HIF-1α stabilization and nuclear translocation for further VEGF expression and release.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. In Vitro Studies
2.1.1. MIO-M1 Cell Culture
2.1.2. Cell Viability/Proliferation
2.1.3. Pharmacological Treatments
2.1.4. Preparation of Conditioned Medium
2.1.5. Quantitative Real-Time PCR
2.1.6. Enzyme-Linked Immunosorbent Assay (ELISA)
2.1.7. Immunofluorescence
2.2. Ex Vivo Studies
2.2.1. Preparation of Retinal Explants
2.2.2. Pharmacological Treatments
2.2.3. Preparation of Conditioned Media
2.2.4. Quantitative Real-Time PCR
2.2.5. ELISA
2.2.6. Immunofluorescence
2.3. Statistics
3. Results
3.1. OS Induces VEGFR2-Dependent VEGF Expression Both in MIO-M1 Cells and in Retinal Explants
3.2. Exogenous VEGF Induces VEGFR2-Dependent VEGF Expression Both in MIO-M1 Cells and in Retinal Explants
3.3. Conditioned Medium Induces VEGF Expression in MIO-M1 Cells
3.4. Conditioned Medium Does Not Induce VEGF Expression in Retinal Explants
3.5. OS Triggers Nrf2 Nuclear Translocation, while OS-Induced VEGF Expression Is Inhibited by Nrf2 Blockade
3.6. Exo-VEGF Has No Effect on Nrf2 Nuclear Translocation, while Exo-VEGF-Induced VEGF Expression Is Not Affected by Nrf2 Blockade
3.7. Blockade of HIF-1 Inhibits VEGF mRNA Expression in All Conditions
4. Discussion
4.1. The Role of OS
4.2. The Involvement of VEGFR2
4.3. The Involvement of Müller Cells
4.4. Intracellular Pathways
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Rossino, M.G.; Lulli, M.; Amato, R.; Cammalleri, M.; Dal Monte, M.; Casini, G. Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy. Cells 2020, 9, 1452. https://doi.org/10.3390/cells9061452
Rossino MG, Lulli M, Amato R, Cammalleri M, Dal Monte M, Casini G. Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy. Cells. 2020; 9(6):1452. https://doi.org/10.3390/cells9061452
Chicago/Turabian StyleRossino, Maria Grazia, Matteo Lulli, Rosario Amato, Maurizio Cammalleri, Massimo Dal Monte, and Giovanni Casini. 2020. "Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy" Cells 9, no. 6: 1452. https://doi.org/10.3390/cells9061452