The BB-rat-an authentic model of human diabetic retinopathy

Sima, Anders A. F.; Chakrabarti, Subrata; Garcia-Salinas, Raul; Basu, P. K.

doi:10.3109/02713688509003353

Cited by 71 publications

(47 citation statements)

References 9 publications

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“…One such factor appears to be the association of specialized vascular smooth muscle cells (i.e., pericytes) with EC tubes (Allt and Lawrenson, 2001;Hellstrom et al, 2001b). Disruption of this interaction is observed in a variety of genetically altered mice (e.g., angiopoietin-1, edg-1, endoglin, and TGF-␤ knockout mice) (Dickson et al, 1995;Suri et al, 1996;Pepper, 1997;Lee et al, 1999;Li et al, 1999;Liu et al, 2000;Urness et al, 2000), as well as in human diabetic retinopathy (Sima et al, 1985;Ruggiero et al, 1997). This disruption causes marked instability of newly formed blood vessels or preexisting vessels.…”

Section: Capillary Tube Formation and Maintenance: A Balance Between mentioning

confidence: 99%

Molecular basis of endothelial cell morphogenesis in three‐dimensional extracellular matrices

2002

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Although many studies have focused on blood vessel development and new blood vessel formation associated with disease processes, the question of how endothelial cells (ECs) assemble into tubes in three dimensions (i.e., EC morphogenesis) remains unanswered. EC morphogenesis is particularly dependent on a signaling axis involving the extracellular matrix (ECM), integrins, and the cytoskeleton, which regulates EC shape changes and signals the pathways necessary for tube formation. Recent studies reveal that genes regulating this matrix-integrin-cytoskeletal (MIC) signaling axis are differentially expressed during EC morphogenesis. The Rho GTPases represent an important class of molecules involved in these events. Cdc42 and Rac1 are required for the process of EC intracellular vacuole formation and coalescence that regulates EC lumen formation in three-dimensional (3D) extracellular matrices, while RhoA appears to stabilize capillary tube networks. Once EC tube networks are established, supporting cells, such as pericytes, are recruited to further stabilize these networks, perhaps by regulating EC basement membrane matrix assembly. Furthermore, we consider recent work showing that EC morphogenesis is balanced by a tendency for newly formed tubes to regress. This morphogenesis-regression balance is controlled by differential gene expression of such molecules as VEGF, angiopoietin-2, and PAI-1, as well as a plasmin-and matrix metalloproteinase-dependent mechanism that induces tube regression through degradation of ECM scaffolds that support EC-lined tubes. It is our hope that this review will stimulate increased interest and effort focused on the basic mechanisms regulating capillary tube formation and regression in 3D extracellular matrices. Anat Rec 268: 252-275, 2002.

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Section: Capillary Tube Formation and Maintenance: A Balance Between mentioning

confidence: 99%

Molecular basis of endothelial cell morphogenesis in three‐dimensional extracellular matrices

2002

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“…Several kinds of rodent model are now available for research into diabetes mellitus. These include the BioBreeding rat [4], the streptozotocin (STZ) rat or alloxan-induced diabetic rat [5] and the non-obese diabetic mouse [6] as models of type 1 diabetes, and the Zucker diabetic fatty rat [7], the BHE (Bureau of Home Economics) rat [8], the OtsukaLong-Evans-Tokushima fatty rat [9] and the diet-induced diabetic rat or mouse as models of type 2 diabetes. Although the majority of these models develop significant diabet-ic retinal microvascular lesions, none have severe retinal changes such as pre-retinal neovascularisation or extensive areas of retinal reperfusion [10].…”

Section: Introductionmentioning

confidence: 99%

Retinal neovascularisation without ischaemia in the spontaneously diabetic Torii rat

Yamada

Higuchi

et al. 2005

Diabetologia

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Aims/hypothesis: The spontaneously diabetic Torii (SDT) rat has recently been established as a model of type 2 human diabetes mellitus. Male SDT rats develop severe diabetic ocular complications. This study investigated the nature of the ocular complications in this model and addressed the question of whether the SDT rat is a good model of human proliferative diabetic retinopathy. Methods: Male SDT rats aged 50 weeks were studied for a period of 8 months. Under deep anaesthesia, one eye of each animal was enucleated following perfusion with fluorescein dextran and a retinal flat mount was prepared to study vascular structure. The other eye was enucleated and investigated histologically by haematoxylin-eosin and azan staining and by immunohistochemistry using antibodies against vascular endothelium (Griffonia simplicifolia isolectin B4 antibody) and vascular endothelial growth factor (VEGF). Results: From the vascular structure study, 17 of 32 rats (53%) showed proliferative retinopathy without vascular non-perfusion. The histological study revealed traction retinal folds in rats with proliferative retinopathy. Azan staining showed some proliferative matrix in rats with normal retinal structure and those with proliferative retinopathy compared with normoglycaemic controls. Staining with Griffonia simplicifolia isolectin B4 antibody showed no specific vascular changes in any of the rats, while VEGF staining revealed higher immunoreactivity in the retina of rats with normal retinal structure and those with proliferative retinopathy, but only low immunoreactivity in the control animals. Conclusions/ interpretation: There appear to be differences between the SDT rat model of diabetic retinopathy and human proliferative diabetic retinopathy, as the SDT rat develops retinal neovascularisation without retinal ischaemia. This very unique display of ocular neovascularisation may be caused by increased expression of VEGF.

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“…This suggests the occurrence of reversible occlusive phenomena. Capillary occlusion by platelet and fibrin thrombi has been noted in the retina of rats with experimental or spontaneous diabetes of at least 8 months' duration (4,5), and stasis of leukocytes in retinal capillaries has been observed as early as a few weeks after induction of experimental diabetes (6,7). Occurrence of capillary thrombosis in human diabetic retinopathy has long been surmised (8,9) but never documented.…”

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confidence: 99%

Increased Prevalence of Microthromboses in Retinal Capillaries of Diabetic Individuals

2001

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In diabetic retinopathy, capillary nonperfusion and eventual obliteration can lead to retinal ischemia and sight-threatening neovascularization. The occurrence of retinal microthrombosis in human diabetes has long been suspected and occasionally observed but never systematically demonstrated. We used trypsin digestion to isolate the intact vascular network from retinas obtained postmortem from nine diabetic donors (age 64 ؎ 11 years, duration of diabetes 6 ؎ 4 years; mean ؎ SD) and eight age-matched nondiabetic donors. Topographically matched sectors (each one-sixth of retina) of diabetic and nondiabetic retinas were tested sequentially with antibodies to fibrin cross-linking factor XIII and platelet glycoprotein (GP)-IIIa to identify fibrinplatelet thrombi. In some trypsin digests, we also examined vascular cell apoptosis. The retina from a nondiabetic donor, 24 years of age, who had died of trauma, was used to exclude confounding influences caused by the postmortem period. When compared with those of nondiabetic donors, the retinas of diabetic donors showed double the number of capillary segments with colocalized immunostaining for factor XIII and GPIIIa (P ‫؍‬ 0.02). The total area of the positive segments was fourfold greater in the diabetic than in the nondiabetic donors (P ‫؍‬ 0.02) and correlated with the duration of diabetes (r ‫؍‬ 0.71, P < 0.05). Large thrombi were six times more frequent in the diabetic donors (P ‫؍‬ 0.03), and there was a significant topographical association of microthrombosis with apoptotic cells in both diabetic and nondiabetic vessels (P ‫؍‬ 0.0001). Hence, diabetes of short duration was found to be associated with a greater than normal number and size of platelet-fibrin thrombi in the retinal capillaries. These thrombi can contribute to capillary obliteration and retinal ischemia and may be a practical target for early drug intervention.

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The BB-rat-an authentic model of human diabetic retinopathy

Cited by 71 publications

References 9 publications

Molecular basis of endothelial cell morphogenesis in three‐dimensional extracellular matrices

Molecular basis of endothelial cell morphogenesis in three‐dimensional extracellular matrices

Retinal neovascularisation without ischaemia in the spontaneously diabetic Torii rat

Increased Prevalence of Microthromboses in Retinal Capillaries of Diabetic Individuals

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