Expression of VLDLR in the Retina and Evolution of Subretinal Neovascularization in the Knockout Mouse Model’s Retinal Angiomatous Proliferation

Hu, Wenzheng; Jiang, Aihua; Ji, Liang; Meng, Hongdi; Chang, Bo; Gao, Hua; Qiao, Xuguang

doi:10.1167/iovs.07-0870

Cited by 101 publications

(119 citation statements)

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“…The pool of bile acids is reduced in Cyp27a1 -/-mice (34, 37); therefore retinal expression of VLDLR could be reduced as well. The caveat is that we do not know whether the FXR-dependent mechanism is operative in the retina, i.e., whether FXR and its mediating partner small heterodimer protein (SHP) are expressed and localized to the same cell types that express VLDLR (90). Moreover, the expression of FXR and SHP was not altered in the liver of Cyp27a1 -/-mice, suggesting that the reduction in the bile acid pool was not sufficient to affect the FXR-mediated regulation of the target genes in this organ (37).…”

Section: Figurementioning

confidence: 99%

Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis

et al. 2012

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Several lines of evidence suggest a link between age-related macular degeneration and retinal cholesterol maintenance. Cytochrome P450 27A1 (CYP27A1) is a ubiquitously expressed mitochondrial sterol 27-hydroxylase that plays an important role in the metabolism of cholesterol and cholesterol-related compounds. We conducted a comprehensive ophthalmic evaluation of mice lacking CYP27A1. We found that the loss of CYP27A1 led to dysregulation of retinal cholesterol homeostasis, including unexpected upregulation of retinal cholesterol biosynthesis. Cyp27a1 -/-mice developed retinal lesions characterized by cholesterol deposition beneath the retinal pigment epithelium. Further, Cyp27a1-null mice showed pathological neovascularization, which likely arose from both the retina and the choroid, that led to the formation of retinal-choroidal anastomosis. Blood flow alterations and blood vessel leakage were noted in the areas of pathology. The Cyp27a1 -/-retina was hypoxic and had activated Müller cells. We suggest a mechanism whereby abolished sterol 27-hydroxylase activity leads to vascular changes and identify Cyp27a1 -/-mice as a model for one of the variants of type 3 retinal neovascularization occurring in some patients with age-related macular degeneration.

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Section: Figurementioning

confidence: 99%

Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis

et al. 2012

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“…This rapid lipid turnover may be an adaptation to photooxidation, because lipids are the most light sensitive of all of the macromolecule classes. Additional evidence for the importance of lipoprotein uptake by the retina has come indirectly from the knockout mice for the LDL ( 62 ) and VLDL receptors ( 63 ), which both exhibit retinal abnormalities. The LDL receptor knockout mice deposit large amounts of lipids in Bruch's membrane, and this seems to lead to photoreceptor loss and retinal degeneration ( 62 ).…”

Section: +2mentioning

confidence: 99%

“…The LDL receptor knockout mice deposit large amounts of lipids in Bruch's membrane, and this seems to lead to photoreceptor loss and retinal degeneration ( 62 ). The VLDL receptor knockouts exhibit extensive neovascularization in the neural retina ( 63 ).…”

Section: +2mentioning

confidence: 99%

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

Rodríguez

Larráyoz

2010

Journal of Lipid Research

120

115

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Journal of Lipid Research Volume 51, 20102847 their actions affect the retina and the retinal pigment epithelium (RPE) ( 8-10 ). One particular oxysterol, 7-ketocholesterol (7KCh), has been found more abundantly than other oxysterols in the retina ( 9, 10 ). This oxysterol is known to have potent pharmacological properties that lead to infl ammation and cell death in a variety of cell types ( 1-10 ). This review will focus on what is known about this molecule and the potential implications of its presence in the retina. The retina is a light-capturing tissue that contains at least 5 cell classes and more than 50 different cell types, each performing unique functions that ultimately provide the visual centers in the brain the information to achieve image formation and visual perception. The retina faces a unique photooxidative environment that generates challenges not encountered by other neurological tissues or organs. Phototransduction requires the retina to have a high metabolic rate ( 11 ) and multiple and complex membrane structures ( 12 ). The photoreceptor outer segments are enriched in the highly photosensitive docosahexaenoic acid and other Abstract This review will discuss the formation and potential implications of 7-ketocholesterol (7KCh) in the retina. 7KCh is a proinfl ammatory oxysterol known to be present in high amounts in oxidized LDL deposits associated with atheromatous plaques. 7KCh is generated in situ in these lipoprotein deposits where it can accumulate and reach very high concentrations. In normal primate retina, 7KCh has been found associated with lipoprotein deposits in the choriocapillaris, Bruch's membrane, and the retinal pigment epithelium (RPE). In photodamaged rats, 7KCh has been found in the neural retina in areas of high mitochondrial content, ganglion cells, photoreceptor inner segments and synapses, and the RPE. Intermediates found by LCMS indicate 7KCh is formed via a free radical-mediated mechanism catalyzed by iron. 7KCh seems to activate several kinase signaling pathways that work via nuclear factor B and cause the induction of vascular endothelial growth factor, interleukin (IL)-6, and IL-8. There seems to be little evidence of 7KCh metabolism in the retina, although some form of effl ux mechanism may be active. The chronic mode of formation and the potent infl ammatory properties of 7KCh indicate it may be an "age-related" risk factor in aging diseases such as atherosclerosis, Alzheimer's, and age-related macular degeneration. -Rodríguez, I. R., and I. M. Larrayoz. Cholesterol oxidation in the retina: implications of 7-KCh formation in chronic infl ammation and age-related macular degeneration. J. Lipid Res . 2010. 51: 2847-2862. Supplementary key words 7-ketocholesterol • cytokines • oxysterolsIn the past year, numerous reviews have been published that extensively discuss the multiple functions of oxysterols and their complex relationships to diseases ( 1-7 ). However, the formation and function of oxysterols in the retina has not been well studied. Emerging studies are...

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“…72 Last, retinal angiomatous proliferation in AMD patients is a relatively uncommon form of neovascularization in which new vessels originate from the inner retinal vasculature and extend through the subretinal space to communicate with the choroidal vessels. This phenotype is replicated in the Vldlr-/-mouse 48 and results in disruption of RPE cells and the Bruch's membrane, retinal-choroidal anastomosis, and subsequent photoreceptor degeneration.…”

Section: Genetically Altered Mouse Models Of Angiogenesismentioning

confidence: 93%

REVIEW PAPER: Animals as Models of Age-Related Macular Degeneration

Zeiss

2010

Vet Pathol

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Age-related macular degeneration (AMD) is a degenerative condition that begins in Bruch's membrane and progresses to involve the retinal pigment epithelium and ultimately the overlying photoreceptors. The only required etiologic factor is age, and AMD is regarded as the leading cause of blindness in individuals older than 65 years. AMD results from variable contributions of age, environment, and genetic predisposition. Many loci are linked to AMD; in the majority of cases, the disease is associated with polymorphisms within these genes, rather than mutations that ablate gene function. The etiologic complexity of AMD is reflected by the paucity of animal models that entirely replicate the human disease. This review compares the salient anatomy of the primate and rodent retina, particularly in the light of AMD pathology. It next discusses prevailing hypotheses explaining how AMD may develop. These include the role of complement activation and macrophage chemotaxis in AMD, molecular mechanisms of choroidal neovascularization, and the roles of oxidative damage and lipid metabolism. Finally, the article gives an overview of spontaneous and induced nonhuman primate models and describes relevant mouse models in the context of each pathogenetic mechanism. KeywordsBruch's membrane, choriocapillaris, complement, degeneration, macula, retinal pigment epithelium Age-related macular degeneration (AMD) is a progressive condition of the retinal pigment epithelium (RPE), its supporting basement membrane, and the overlying photoreceptor layer. It affects the macula, the central area of the retina responsible for high-acuity daylight vision. Among individuals older than 65 years, AMD is regarded as the leading cause of blindness in the industrialized world. 39AMD has no single cause and results from variable contributions of age, genetic predisposition, and environment. Established epidemiologic risk factors include cigarette smoking, diet, female sex, Caucasian race, and a family history of AMD.52,60,61 Because AMD is rare in individuals younger than 55 years, the only required risk factor is age, which implicates the multitude of cellular changes that accompany normal aging in the pathogenesis of AMD. The challenge is to identify how these are altered to tip the process toward overt disease.With age, most people accumulate small, well-demarcated deposits of extracellular material beneath the RPE. 5,45 These are known as small, hard drusen and are not pathogenic. However, if these deposits enlarge, they become associated with regional RPE loss and eventual degeneration of overlying photoreceptors. These changes are funduscopically visible, and their progression is used to classify lesions along the continuum of early to late dry AMD. 18 The pathogenetic mechanisms of this process center on inflammation, oxidative damage, and RPE senescence 45 and are predominantly modeled in the mouse.In the minority of cases, late AMD is accompanied by growth of blood vessels from the choroid through Bruch's membrane toward the retina. ...

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Expression of VLDLR in the Retina and Evolution of Subretinal Neovascularization in the Knockout Mouse Model’s Retinal Angiomatous Proliferation

Abstract: VLDLR is expressed in the wild-type mouse retina, especially in RECs and RPE cells. The vldlr(-/-) mouse exhibits histologic and angiographic characteristics of RAP and is a reproducible animal model facilitating studies of the molecular mechanisms of RAP.

Cited by 101 publications

References 38 publications

Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis

Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

REVIEW PAPER: Animals as Models of Age-Related Macular Degeneration

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