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Yun-Zheng Le, Mei Zhu; Synergistic effect among BDNF, GDNF, or VEGF on protecting Müller cells in hypoxia: implication in neuroprotection in age-related macular degeneration and diabetic retinopathy and in anti-VEGF therapies. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5398.
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© ARVO (1962-2015); The Authors (2016-present)
To study the mechanism of Müller glia (MG) in neuroprotection in hypoxic retinal diseases, we generated a hypoxia-induced MG ablation model by genetic disrupting Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) in mice, and investigated the effect and mechanism of on VEGFR2 disruption on MG loss, trophic factor production, and neuroprotection under hypoxic conditions.
The mouse model was generated by conditional disrupting VEGFR2 in MG. The hypoxia-induced MG ablation was achieved by inducing hypoxia with cobalt chloride in conditional VEGFR2 knockout mice. MG density was evaluated with immunohistochemistry. Retinal morphology was assessed in hematoxylin & eosin (H&E) stained sections. Gene expression was analyzed with immunoblotting. Interaction of trophic factors in promoting MG viability was investigated with a rat cell line rMC1.
While there was no apparent alteration in retinal morphology and cell density under normal conditions, the conditional VEGFR2 knockout mice demonstrated a significant loss of MG and retinal neuronal density in hypoxia, which coincided with a substantial reduction of retinal Glial cell line-Derived Neurotrophic Factor (GDNF) and Brain-Derived Neurotrophic Factor (BDNF). Rescuing MG and neuronal degeneration in hypoxic conditional VEGFR2 knockout mice is in progress. Mechanistic investigation suggests that BDNF, GDNF, and VEGF may support MG viability act in a synergistic fashion under hypoxic condition.
MG are vulnerable in hypoxic retina. VEGF, in conjunction with BDNF and/or GDNF, may play a prominent role in protecting MG in hypoxic retina, which is critical to neuroprotection under this pathological condition. As the degenerative retinas in hypoxic conditional VEGFR2 knockout mice bear striking resemblance to the abnormally thin retinas in a significant portion of patients in 5-year anti-VEGF clinical trials for neovascular age-related macular degeneration (AMD), our work may have a significant implication in neuroprotective strategies in hypoxic retinal diseases, such as AMD and diabetic retinopathy, and in designing safer anti-VEGF therapies for these leading causes of blindness.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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