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J. Biol. Chem., Vol. 282, Issue 47, 34420-34428, November 23, 2007

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Very Low Density Lipoprotein Receptor, a Negative Regulator of the wnt Signaling Pathway and Choroidal Neovascularization^*

Ying Chen, Yang Hu, Kangmo Lu, John G. Flannery, and Jian-xing Ma¹

From the Department of Cell Biology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104 and Vision Science and the Neuroscience Division, Department of Molecular and Cell Biology, The Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720-3192

Choroidal neovascularization (CNV) in age-related macular degeneration is a leading cause of blindness. Very low density lipoprotein receptor gene knock-out (Vldlr^-/-) mice have been shown to develop subretinal neovascularization (NV) with an unknown mechanism. The present study showed that in Vldlr^-/- mice, NV initiated in the choroid and progressed to penetrate the retinal pigment epithelium layer, proliferating in the subretinal space. This phenotype recapitulated what is seen in wet age-related macular degeneration, suggesting that this is a CNV model. The CNV correlated with overexpression of vascular endothelial growth factor in Vldlr^-/- eyecups and was blocked by a neutralizing antibody against vascular endothelial growth factor receptor-2. The wnt co-receptor LRP5/6 expression was significantly up-regulated in Vldlr^-/- eyecups compared with that in wild-type mice. Significantly, Vldlr^-/- mice showed impaired phosphorylation of downstream effectors of the wnt signaling pathway, glycogen synthase kinase-3 (GSK-3), and -catenin, concomitant with increased levels of free GSK-3 and -catenin, suggesting an increased activity of the wnt pathway. Down-regulation of VLDLR by small interference RNA resulted in up-regulation of LRP5/6 expression and activation of -catenin in cultured endothelial cells. Furthermore, Dickkopf-1, a specific inhibitor of the wnt pathway, effectively decreased vascular endothelial growth factor and -catenin levels in the retinal pigment epithelium of Vldlr^-/- mice and in cells transfected with the VLDLR small interference RNA. These results suggest that VLDLR functions as a negative regulator of CNV, and this function is mediated through the wnt pathway.

Received for publication, December 8, 2006 , and in revised form, September 17, 2007.

^* This study was supported by National Institutes of Health Grants EY012231 and EY015650 and grants from the American Diabetes Association, Juvenile Diabetes Research Foundation, Oklahoma Center for the Advancement of Science and Technology, and a Diabetes and Vision COBRE (to Oklahoma University of Health Sciences Center). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 941 Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK 73104. Tel.: 405-271-4372; Fax: 405-271-3973; E-mail: jian-xing-ma{at}ouhsc.edu.

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