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Originally published In Press as doi:10.1167/iovs.08-2591 on December 20, 2008
 (Investigative Ophthalmology and Visual Science. 2009;50:1873-1879.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-2591
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Role of PI3K/Akt and MEK/ERK in Mediating Hypoxia-Induced Expression of HIF-1{alpha} and VEGF in Laser-Induced Rat Choroidal Neovascularization

Xiu-Mei Yang,1 Yu-Sheng Wang,1 Jian Zhang,2 Yan Li,2 Jian-Feng Xu,1 Jie Zhu,1 Wei Zhao,1 Da-Ke Chu,3 and Peter Wiedemann4

1From the Department of Ophthalmology, Eye Institute of Ophthalmology of Chinese PLA, Xijing Hospital, the 2Department of Biochemistry and Molecular Biology, and the 3Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China; and the 4Eye Hospital, University of Leipzig, Leipzig, Germany.

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-1{alpha}. Hypoxia plays an important role in the development of choroidal neovascularization (CNV). Expression of HIF-1{alpha} 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-1{alpha} 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-1{alpha} 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-1{alpha}, and VEGF were upregulated in vivo and in vitro. PI3K inhibitor (Ly294002) significantly decreased pAkt activity and HIF-1{alpha} 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-1{alpha}. LY294002 and PD98059 severely inhibited the formation of CNV.

CONCLUSIONS. The PI3K/Akt pathway was required for hypoxia-induced expression of HIF-1{alpha} and VEGF, whereas the MEK/ERK pathway was required only for VEGF in laser-induced rat CNV.






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