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Jeong Hun Kim, Jin Hyoung Kim, Sung Wook Park, Noo Li Jeon, Young S. Yu; Hypoxia-induced Insulin-like Growth Factor II Contributes to Retinal Vascularization in Ocular Development. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2542.
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In ocular development, retinal physiological hypoxia in response to the retinal metabolic activity controls retinal vascular development, which is regulated by variable angiogenic factors. Herein, we demonstrated that hypoxia-induced IGF-II could contribute to retinal vascularization in ocular development.
In developing mouse, immunohistochemistry for IGF-II as well as immunofluorescence staining of IGF-II with vWF were performed. In human retinal microvascular endothelial cells (HRMEC), IGF-2 and VEGF expression were measured by RT-PCR and Western blot analysis under hypoxic condition (1%). To investigate IGF-2 induced regulation of VEGF expression in HRMEC, western blot analysis for VEGF, ERK-1/2, p-ERK-1/2, Akt, and p-Akt was performed with treatment of IGF-II. In addition, VEGF expression in HRMEC was evaluated under hypoxia with treatment of a blocking antibody to IGF-2 by RT-PCR and Western blot analysis. To confirm the direct angiogenic activity of IGF-II, angiogenesis assays of migration & tube formation was performed as well.
In the developing retina, IGF-II expression appears to be predominant on retinal vessels, which was chronologically increased and peaked during active retinal angiogenesis similar to VEGF expression. Under hypoxic condition, IGF-II as well as VEGF was significantly up-regulated in HRMEC. In addition, IGF-II treatment could also increase VEGF expression in HRMEC. The VEGF expression induced by IGF-II was mediated by ERK-1/2 activation. Moreover, IGF-II strongly promoted angiogenic processes of migration and tube formation of HRMEC.
Our results provided that hypoxia-induced IGF-II may regulate retinal vascular development not only directly by IGF-II-mediated angiogenic activity, but also indirectly by IGF-II-induced VEGF expression. Therefore, the potential contribution of IGF-II to pathological retinal angiogenesis should be furthermore explored for the development of novel treatments to vaso-proliferative retinopathies.
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