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

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.

[1]  G. A. Limb,et al.  In vitro response and gene expression of human Retinal Müller cells treated with different Anti-VEGF drugs. , 2020, Experimental eye research.

[2]  Giovanni Casini,et al.  Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy , 2019, Front. Neurosci..

[3]  S. Langdon,et al.  Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies , 2019, Cancer drug resistance.

[4]  Q. Ren,et al.  Baicalin relieves hypoxia-aroused H9c2 cell apoptosis by activating Nrf2/HO-1-mediated HIF1α/BNIP3 pathway , 2019, Artificial cells, nanomedicine, and biotechnology.

[5]  S. D. De Smedt,et al.  Müller cells as a target for retinal therapy. , 2019, Drug discovery today.

[6]  Giovanni Casini,et al.  Nutraceuticals for the Treatment of Diabetic Retinopathy , 2019, Nutrients.

[7]  M. Cammalleri,et al.  Lisosan G Protects the Retina from Neurovascular Damage in Experimental Diabetic Retinopathy , 2018, Nutrients.

[8]  K. Martin,et al.  Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies , 2018, Expert opinion on biological therapy.

[9]  Jin Yao,et al.  Gαi1 and Gαi3mediate VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis , 2018, Theranostics.

[10]  Matthew Slattery,et al.  Identification of a functional antioxidant response element at the HIF1A locus , 2018, Redox biology.

[11]  Yoon Kyung Choi,et al.  Heme oxygenase metabolites improve astrocytic mitochondrial function via a Ca2+-dependent HIF-1α/ERRα circuit , 2018, PloS one.

[12]  M. Lulli,et al.  Nanoparticle-Mediated Delivery of Neuroprotective Substances for the Treatment of Diabetic Retinopathy , 2018, Current neuropharmacology.

[13]  Wei Wang,et al.  Diabetic Retinopathy: Pathophysiology and Treatments , 2018, International journal of molecular sciences.

[14]  P. Fort,et al.  Role of Inflammation in Diabetic Retinopathy , 2018, International journal of molecular sciences.

[15]  D. Tuveson,et al.  Transcriptional Regulation by Nrf2 , 2017, Antioxidants & redox signaling.

[16]  Y. Wada,et al.  The roles of signal transducer and activator of transcription factor 3 in tumor angiogenesis , 2017, Oncotarget.

[17]  A. Sholl-Franco,et al.  Cellular stress response in human Müller cells (MIO‐M1) after bevacizumab treatment , 2017, Experimental eye research.

[18]  Y. Le VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases , 2017, Vision Research.

[19]  A. Ferrigno,et al.  Autocrine and Paracrine Secretion of Vascular Endothelial Growth Factor in the Pre-Hypoxic Diabetic Retina. , 2017, Current diabetes reviews.

[20]  M. Mishra,et al.  Epigenetic regulation of redox signaling in diabetic retinopathy: Role of Nrf2 , 2017, Free radical biology & medicine.

[21]  Han-dong Wang,et al.  Interplay between VEGF and Nrf2 regulates angiogenesis due to intracranial venous hypertension , 2016, Scientific Reports.

[22]  J. Mercer,et al.  VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis , 2016, Journal of Cell Science.

[23]  M. Ferrer,et al.  Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors. , 2016, ACS chemical biology.

[24]  Mieke Dewerchin,et al.  Vascular endothelial growth factor: a neurovascular target in neurological diseases , 2016, Nature Reviews Neurology.

[25]  M. Cammalleri,et al.  VEGF as a Survival Factor in Ex Vivo Models of Early Diabetic Retinopathy. , 2016, Investigative ophthalmology & visual science.

[26]  R. Simó,et al.  Neuroprotection as a Therapeutic Target for Diabetic Retinopathy , 2016, Journal of diabetes research.

[27]  A. Bullock,et al.  Structural basis of Keap1 interactions with Nrf2 , 2015, Free radical biology & medicine.

[28]  T. Behl,et al.  Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy. , 2015, Pharmacological research.

[29]  Y. Le,et al.  Müller Glia Are a Major Cellular Source of Survival Signals for Retinal Neurons in Diabetes , 2015, Diabetes.

[30]  C. Costagliola,et al.  Diabetic Retinopathy: Vascular and Inflammatory Disease , 2015, Journal of diabetes research.

[31]  E. Borsi,et al.  Therapeutic targeting of hypoxia and hypoxia-inducible factor 1 alpha in multiple myeloma. , 2015, Translational research : the journal of laboratory and clinical medicine.

[32]  Sergio Capaccioli,et al.  A pathophysiological view of the long non-coding RNA world , 2014, Oncotarget.

[33]  Xianming Deng,et al.  Dihydroartemisinin targets VEGFR2 via the NF-κB pathway in endothelial cells to inhibit angiogenesis , 2014, Cancer biology & therapy.

[34]  Xin Xie,et al.  Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug, promotes embryonic stem cell self-renewal and somatic cell reprogramming , 2014, Cell Research.

[35]  Tetsuro Ohba,et al.  Autocrine VEGF/VEGFR1 Signaling in a Subpopulation of Cells Associates with Aggressive Osteosarcoma , 2014, Molecular Cancer Research.

[36]  Xian-min Xiao,et al.  Upregulated autocrine vascular endothelial growth factor (VEGF)/VEGF receptor‐2 loop prevents apoptosis in haemangioma‐derived endothelial cells , 2014, The British journal of dermatology.

[37]  F. Agani,et al.  Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. , 2013, Current Cancer Drug Targets.

[38]  J. Roider,et al.  Regulation of constitutive vascular endothelial growth factor secretion in retinal pigment epithelium/choroid organ cultures: p38, nuclear factor kappaB, and the vascular endothelial growth factor receptor-2/phosphatidylinositol 3 kinase pathway , 2013, Molecular vision.

[39]  E. Catalani,et al.  Vascular endothelial growth factor in the ischemic retina and its regulation by somatostatin , 2012, Journal of neurochemistry.

[40]  P. Bagnoli,et al.  Mechanisms underlying somatostatin receptor 2 down‐regulation of vascular endothelial growth factor expression in response to hypoxia in mouse retinal explants , 2012, The Journal of pathology.

[41]  T. Pufe,et al.  Interplay between Vascular Endothelial Growth Factor (VEGF) and Nuclear Factor Erythroid 2-related Factor-2 (Nrf2) , 2011, The Journal of Biological Chemistry.

[42]  A. Zannettino,et al.  The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma , 2011, Leukemia.

[43]  A. Balbarini,et al.  Hypoxia effects on proangiogenic factors in human umbilical vein endothelial cells: functional role of the peptide somatostatin , 2011, Naunyn-Schmiedeberg's Archives of Pharmacology.

[44]  Sheng-Kwei Song,et al.  Vitreous Volume of the Mouse Measured by Quantitative High-Resolution MRI , 2010 .

[45]  H. Lee,et al.  Vascular endothelial growth factor as an autocrine survival factor for retinal pigment epithelial cells under oxidative stress via the VEGF-R2/PI3K/Akt. , 2010, Investigative ophthalmology & visual science.

[46]  Magali Saint-Geniez,et al.  Endogenous VEGF Is Required for Visual Function: Evidence for a Survival Role on Müller Cells and Photoreceptors , 2008, PloS one.

[47]  M. Bartoli,et al.  Vascular endothelial growth factor in eye disease , 2008, Progress in Retinal and Eye Research.

[48]  Kazuhiro Takahashi,et al.  Fasudil-induced hypoxia-inducible factor-1α degradation disrupts a hypoxia-driven vascular endothelial growth factor autocrine mechanism in endothelial cells , 2008, Molecular Cancer Therapeutics.

[49]  C. Caramelo,et al.  Induction of Hypoxia-inducible Factor 1α Gene Expression by Vascular Endothelial Growth Factor* , 2008, Journal of Biological Chemistry.

[50]  Kenneth P. Roos,et al.  Autocrine VEGF Signaling Is Required for Vascular Homeostasis , 2007, Cell.

[51]  Mikko Nikinmaa,et al.  Oxygen-dependent diseases in the retina: role of hypoxia-inducible factors. , 2006, Experimental eye research.

[52]  C. Caramelo,et al.  Mechanisms of endothelial response to oxidative aggression: protective role of autologous VEGF and induction of VEGFR2 by H2O2. , 2006, American journal of physiology. Heart and circulatory physiology.

[53]  F. Orsenigo,et al.  Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments , 2006, The Journal of cell biology.

[54]  M. Bartoli,et al.  VEGF differentially activates STAT3 in microvascular endothelial cells , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  Jong-Wan Park,et al.  Oxygen-dependent and -independent regulation of HIF-1alpha. , 2002, Journal of Korean medical science.

[56]  B. Terman,et al.  Autophosphorylation of KDR in the kinase domain is required for maximal VEGF-stimulated kinase activity and receptor internalization , 1999, Oncogene.

[57]  Y. Le,et al.  VEGF as a Trophic Factor for Müller Glia in Hypoxic Retinal Diseases. , 2018, Advances in experimental medicine and biology.

[58]  M. Friedlander,et al.  Hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) signaling in the retina. , 2014, Advances in experimental medicine and biology.

[59]  J. Roider,et al.  Mechanisms of Pathological VEGF Production in the Retina and Modification with VEGF-Antagonists , 2012 .