Therefore, LRP6, VEGF and VLDLR have been suggested to play roles in the development of AMD ( Haines et al., 2006). VLDLR showed evidence of association in both the family-based and case-control datasets. VEGF showed evidence of linkage and demonstrated significant independent allelic association in both the family-based and case-control datasets. LRP6 showed linkage in the family-based dataset and association in the case-control dataset. A recent study of genetic linkage and allelic association has identified three genes, the very low-density lipoprotein receptor (VLDLR), VEGF and low-density lipoprotein receptor-related protein-6 (LRP6), with significant linkage or association to AMD ( Haines et al., 2006). The pathway mediating inflammation in AMD has not been defined. Additionally, patients with severe wet AMD have several characteristics of chronic inflammatory diseases, such as elevated levels of tumor necrosis factor-О± (TNF-О±), soluble ICAM-1, and circulating vascular cell adhesion molecule-1 (VCAM-1), which attributes to manifestation of local edema ( Bok, 2005). ICAM-1 is a major adhesion molecule leading to leukostasis in the retina ( Miyamoto et al., 2000). VEGF functions not only as an angiogenic factor, but also as a pro-inflammatory and permeability factor ( Croll et al., 2004 Dvorak, 2000 Ishida et al., 2003 Usui et al., 2004 Vinores et al., 2001). Over-expression of pro-inflammatory factors such as VEGF and intercellular adhesion molecule-1 (ICAM-1) has been shown to play a key role in retinal inflammation and CNV. The recent breakthrough in genetic studies has shown that complement factor H plays a critical role in the pathogenesis of AMD, further supporting the pathogenic role of inflammation in AMD ( Edwards et al., 2005 Klein et al., 2005 Nozaki et al., 2006). Increased oxidative stress and inflammation in the retina are believed to play a pathogenic role in AMD ( Ambati et al., 2003 Gong et al., 2001 Schlingemann, 2004). CNV is a major vision threatening complication of AMD ( Provis et al., 2005).ДЄMD is a complex disorder involving multiple genes and risk factors. The abnormal neovasculature has high permeability, which can lead to macular edema and macrophage infiltration. In the wet AMD, abnormal neovasculature, originated from the choroid, forms either beneath the retinal pigment epithelium (RPE) or in the subretinal space after penetration through BruchвЂ™s membrane, forming choroidal neovascularization (CNV). The dry AMD is characterized by geographic atrophy, cone degeneration and loss of cone functions. At late stages, AMD appears in two major forms, the dry AMD and wet AMD. At early stages, AMD is characterized by generation of drusen in the macular area and hyper- or hypo-pigmentation of the RPE ( Bylsma, 2005 Provis et al., 2005). AMD is a chronic and progressive retinal degenerative disease. The prevalence of AMD increases exponentially with age ( Ambati et al., 2003 Nowak, 2006). These findings suggest that deficiency of VLDLR leads to retinal degeneration and inflammation.ДЄge-related macular degeneration (AMD) is the leading cause of blindness in the developed countries. Moreover, Vldlr в€’/в€’ mice displayed up-regulated expression of multiple pro-inflammatory factors and activated NF-ОєB and HIF-1О±, key regulators of inflammation. Staining of adherent leukocytes in the retinal vasculature revealed significant leukostasis in Vldlr в€’/в€’ mice. Double staining of pericytes and endothelial cells in retinal sections revealed that neovasculature in Vldlr в€’/в€’ mice lacks pericyte coverage, suggesting impaired maturation of retinal vasculature in Vldlr в€’/в€’ mice. ZO-1, a tight junction protein, was down-regulated in Vldlr в€’/в€’ mouse retinae, further supporting the impaired blood-retinal barrier. As shown by fluorescein angiography and permeability assay, Vldlr в€’/в€’ mice had severe retinal vascular leakage. At older ages, Vldlr в€’/в€’ mice displayed declined rod ERG responses, decreased layers of photoreceptor nuclei, reduced rhodopsin levels and decreased levels of 11- cis retinal, the chromophore of visual pigments. Immunostaining of mid-wavelength cones showed significantly decreased cone densities in the retina and shortened cone outer segments in Vldlr в€’/в€’ mice. The present study showed that VLDLR gene knockout ( Vldlr в€’/в€’) mice displayed impaired cone ERG responses at early ages. Our previous studies have shown that very low-density lipoprotein receptor (VLDLR) is a negative regulator of the Wnt pathway.

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