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Xiu-Mei Yang, Yu-Sheng Wang, Jian Zhang, Yan Li, Jian-Feng Xu, Jie Zhu, Wei Zhao, Da-Ke Chu, Peter Wiedemann; Role of PI3K/Akt and MEK/ERK in Mediating Hypoxia-Induced Expression of HIF-1α and VEGF in Laser-Induced Rat Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2009;50(4):1873-1879. doi: 10.1167/iovs.08-2591.
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purpose. The transcription factor hypoxia-inducible factor (HIF)-1 plays a central physiological role in oxygen and energy homeostasis and is activated during hypoxia by stabilization of the subunit HIF-1α. Hypoxia plays an important role in the development of choroidal neovascularization (CNV). Expression of HIF-1α has been demonstrated in CNV. Vascular endothelial growth factor (VEGF) is one of the most well-characterized angiogenic factors in CNV, which is under the regulation of HIF-1. The aim of the present study was to explore the upstream signaling pathways involved in regulating hypoxia-induced expression of HIF-1α and VEGF in laser-induced rat CNV.
methods. A well-established rat model of CNV and cultured human retinal pigment epithelium (hRPE) was used to investigate the role of PI3K/Akt and MEK/ERK pathways in regulating HIF-1α and VEGF expression in CNV in rat and hRPE under hypoxia by immunohistochemistry, Western blot analysis, real-time PCR, and ELISA.
results. pAkt, pERK, HIF-1α, and VEGF were upregulated in vivo and in vitro. PI3K inhibitor (Ly294002) significantly decreased pAkt activity and HIF-1α and VEGF expression in vivo and in vitro, whereas MEK inhibitor (PD98059) reduced ERK phosphorylation and the expression of VEGF but had no effect on HIF-1α. LY294002 and PD98059 severely inhibited the formation of CNV.
conclusions. The PI3K/Akt pathway was required for hypoxia-induced expression of HIF-1α and VEGF, whereas the MEK/ERK pathway was required only for VEGF in laser-induced rat CNV.
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