Increased expression of vascular endothelial growth factor associated with accumulation of lipids in Bruch's membrane of LDL receptor knockout mice

Abstract

Aim: To investigate the pathogenesis of age related macular degeneration (ARM) with respect to lipid accumulation within Bruch's membrane (BrM) in a knockout model with low density lipoprotein (LDL) receptor deficiency. Methods: LDL receptor deficient mice and C57BL/6 controls were fed a standard diet or a high fat (HF) diet. Plasma total cholesterol (pTC) was determined. Eyes were examined by transmission electron microscopy. Immunohistochemical staining for VEGF was performed. Results: pTC were highest in LDL receptor deficient mice after HF diet and elevated after standard diet compared to controls with and without HF diet. While BrM of controls did not exhibit any visible changes, membrane bound translucent particles were seen in all BrM of knockout mice. The amount of these particles was substantially increased and membranes were thickened after HF diet. VEGF staining was positive in knockout mice only and was located in retinal pigment epithelial cells, the outer plexiform layer, and photoreceptor inner segments. Most intensive VEGF expression was documented after HF diet. Conclusion: LDL receptor deficient mice exhibit an accumulation of lipid particles in BrM which is further increased after fat intake. VEGF expression is found in the outer retinal layers of LDL receptor deficient mice and appears to correlate with the amount of lipid particles present in BrM.

Dietary fatty acids and lipoproteins on progression of age-related macular degeneration

“…Sub-RPE lipid deposits are involved in the pathogenesis of AMD (Curcio et al, 2009). Furthermore, a high-fat diet also promoted the occurrence of thickening, membrane-bound translucent particles, and immunolocalization of VEGF in Brunch's membrane of LDLR -/-mice, supporting the notion of accelerated AMD under decreased LDL clearance (Rudolf et al, 2005). These studies suggesting that lipoprotein accumulation in RPE, synergistic with hyperlipidaemia and associated with a high-fat diet, is related to AMD pathogenesis.…”

Vascular endothelial growth factor in eye disease

“…However, the connection between dietary fat, lipids, and VEGF is less clear. Some evidence is provided by the LDL receptor knockout mice that accumulate lipid in Bruch's membrane and have increased immunoreactivity of VEGF in the RPE, outer plexiform layer, and photoreceptor inner segments, particularly after mice are fed a high fat diet (Rudolf et al, 2005). Also, recombinant Apo-E4 suppressed Ccl-2 and VEGF expression by human RPE and suggested a mechanism by which apolipoproteins can differentially regulate chemokines and VEGF in AMD (Bojanowski et al, 2006).…”

Aumento da imunorreatividade ao VEGFR-1 no complexo coroido-escleral em modelo experimental de hipercolesterolemia

“…O acúmulo de lipídeos na MB foi considerado responsável pelas modi ficações anatômicas destas estruturas, hipóxia e pelo consequente aumento da expressão do VEGF na coriocapilar (22) . Outro estudo experimental também atribuiu à deposição de partículas lipídicas na MB o aumento da imunorreatividade do VEGF na membrana basal das células do EPR, camada plexiforme externa e segmentos internos dos fotorrecepetores (23) . No presente estudo, observouse significa tiva imunorreatividade ao VEGFR1 do complexo coroidoescleral Tabela 1.…”

“…Este estudo fortalece a idéia de que a DMRI e a aterosclerose compartilham mecanismos fisiopatogê nicos similares, e que a hipercolesterolemia é uma fator modificável da DMRI (9,12) . Adicionalmente, os estudos experimentais, incluindo o presente relato, que visaram simular a DMRI humana, utilizaram o aumento do colesterol sérico para provocar deposição lipídica na MB e aumento da expressão do VEGF (22,23,28) . Ao escolher coelhos para esta pesquisa, foram ponderadas as vantagens desse animal sobre os demais, que incluem mais disponi bilidade, baixo custo (em relação a camundongos transgênicos defi cientes dos receptores para o colesterol LDL ou apoliproteína E) e a caracterização genética mais definida (29) .…”