Vascular basement membrane changes in diabetic retinopathy. Montgomery lecture, 1973.

Ashton, Norman

doi:10.1136/bjo.58.4.344

Cited by 163 publications

(80 citation statements)

References 34 publications

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“…V ascular basement membrane (BM) thickening is a fundamental structural abnormality of diabetic microangiopathy (1)(2)(3)(4)(5). In diabetes, vascular BM thickening is a slowly developing process when extracellular matrix (ECM) accumulation occurs.…”

mentioning

confidence: 99%

Downregulation of Fibronectin Overexpression Reduces Basement Membrane Thickening and Vascular Lesions in Retinas of Galactose-Fed Rats

et al. 2003

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Overexpression of extracellular matrix (ECM) components is closely associated with the development of vascular basement membrane (BM) thickening, a histological hallmark of diabetic microangiopathy. To determine whether BM thickening of retinal capillaries could be prevented by down regulating synthesis of fibronectin, an ECM component, we used antisense oligos targeted against translation initiation site of the fibronectin transcript in galactose-fed rat, an animal model of diabetic retinopathy. After 2 months of galactose-feeding, intravitreal administration of 3 mol/l antisense fibronectin oligos was initiated at monthly intervals for 3 months. The antisense strategy significantly reduced fibronectin mRNA and protein level in the retinas of treated eyes compared with untreated eyes of galactose-fed rats (130 ؎ 16 vs. 179 ؎ 18% of control, P < 0.01, and 144 ؎ 28 vs. 204 ؎ 22% of control, respectively, r ‫؍‬ 0.9) and resulted in partial reduction of retinal capillary BM width (123 ؎ 16 vs. 201 ؎ 12 nm, P < 0.03). In eyes treated with antisense fibronectin oligos, ϳ35% reduction in both pericyte loss and acellular retinal capillaries was observed (P < 0.04 and P < 0.03, respectively). Glycohemoglobin level was consistently elevated in the treated (6.9 ؎ 0.6%) and untreated (6.5 ؎ 0.7%) galactose-fed rats compared with control rats (4.5 ؎ 0.8%). Overall, these results indicate that downregulation of fibronectin synthesis reduces BM thickening in retinal capillaries with beneficial effect to retinal lesions. The antisense fibronectin oligos may provide a useful approach for reducing vascular lesions in diabetic retinopathy. The thickened vascular BM may be a potential therapeutic target for preventing retinal lesions in diabetic retinopathy. Diabetes 52: 1229 -1234, 2003

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confidence: 99%

Downregulation of Fibronectin Overexpression Reduces Basement Membrane Thickening and Vascular Lesions in Retinas of Galactose-Fed Rats

et al. 2003

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“…ncreased synthesis of basement membrane components, fibronectin, collagen IV, and laminin is closely associated with vascular basement membrane thickening, a histological hallmark of diabetic retinopathy (1)(2)(3)(4)(5). In vivo and in vitro studies have shown that diabetes selectively increases basement membrane gene expression in retinal vascular cells and that the excess synthesis of basement membrane components contributes, at least in part, to the development of thickened vascular basement membranes (6 -9).…”

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confidence: 99%

Effect of Combined Antisense Oligonucleotides Against High-Glucose–and Diabetes-Induced Overexpression of Extracellular Matrix Components and Increased Vascular Permeability

et al. 2006

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The effect of combined antisense oligonucleotides (ASoligos) against overexpression of extracellular matrix (ECM) components, fibronectin, laminin, and collagen IV and on cell monolayer permeability was examined in rat microvascular endothelial cells (RMECs) grown in high glucose medium and on retinal vascular permeability in diabetic rats. RMECs grown in high glucose for 10 days and transfected with combined AS-oligos showed a significantly reduced fibronectin, laminin, and collagen IV protein level. In parallel studies, high-glucose-induced excess monolayer permeability was also reduced in RMECs transfected with the combined AS-oligos. Similarly, diabetic rats intravitreally injected with the combined AS-oligos and examined after 2 months of diabetes showed significant reduction in retinal fibronectin, laminin, and collagen IV expression. In addition, vascular permeability, as determined from extravasation of fluorescein isothiocyanate-BSA in the surrounding areas of the retinal capillaries, was partially reduced in the combined AS-oligos-treated diabetic retinas. Our results indicate that the combined AS-oligos strategy is effective in simultaneously reducing fibronectin, collagen IV, and laminin overexpression and reducing vascular leakage in the retinal capillaries of diabetic rat retinas. The findings suggest that abnormal synthesis of ECM components may contribute to vascular leakage in the diabetic retina. Diabetes 55: 86 -92, 2006

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“…Insudative haematogenous constituents possibly contribute to the thickening (Ashton 1974), and a demonstration that the basement membrane changes in streptozotocin-diabetic rats are preceded by increased endothelial cell permeability (Ishibashi et al 1979) is suggestive of a causal relationship. However, a real increase in collagenous tissue is also probable.…”

Section: Pathophysiology -Preliminary Stagementioning

confidence: 99%

Developments in the Pathology of Diabetic Retinopathy: A Review

Garner

1981

J R Soc Med

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Vascular basement membrane changes in diabetic retinopathy. Montgomery lecture, 1973.

Cited by 163 publications

References 34 publications

Downregulation of Fibronectin Overexpression Reduces Basement Membrane Thickening and Vascular Lesions in Retinas of Galactose-Fed Rats

Downregulation of Fibronectin Overexpression Reduces Basement Membrane Thickening and Vascular Lesions in Retinas of Galactose-Fed Rats

Effect of Combined Antisense Oligonucleotides Against High-Glucose–and Diabetes-Induced Overexpression of Extracellular Matrix Components and Increased Vascular Permeability

Developments in the Pathology of Diabetic Retinopathy: A Review

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