A Morphologic and Autoradiographic Study of Cell Death and Regeneration in the Retinal Microvasculature of Normal and Diabetic Rats

Sharma, Neeraj; Gardiner, Tom; Archer, D. B.

doi:10.1016/s0002-9394(14)74982-7

Cited by 80 publications

(45 citation statements)

References 10 publications

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“…Endothelial cell death and proliferation are known to proceed simultaneously in the diabetic human retina. 15 We speculate that replicative senescence eventually tips the balance in favor of endothelial cell death.…”

Section: Discussionmentioning

confidence: 94%

Leukocyte-Mediated Endothelial Cell Injury and Death in the Diabetic Retina

Joussen

Murata

Tsujikawa

et al. 2001

The American Journal of Pathology

512

394

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Endothelial cell death is a hallmark of diabetic retinopathy. Its occurrence is required for the formation of acellular (devitalized) capillaries, lesions that produce irreversible retinal ischemia through their inability to support blood flow. The mechanisms underlying diabetic retinal endothelial cell injury and death remain largely unknown. The current study demonstrates that adherent leukocytes are temporally and spatially associated with retinal endothelial cell injury and death within 1 week of streptozotocin-induced experimental diabetes in rats. Moreover, the antibody-based neutralization of intercellular adhesion molecule-1 and CD18 is shown to prevent both leukocyte adhesion and retinal endothelial cell injury and death. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-intercellular adhesion molecule1-and anti-CD18-based therapies in the treatment of diabetic retinopathy, a newly recognized inflammatory disease.

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Section: Discussionmentioning

confidence: 94%

Leukocyte-Mediated Endothelial Cell Injury and Death in the Diabetic Retina

Joussen

Murata

Tsujikawa

et al. 2001

The American Journal of Pathology

512

394

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“…In turn, ischemia reperfusion appears to cause an exaggerated inflammatory response in diabetic microvessels (31). Lastly, vascular endothelium already challenged by hyperglycemia (38) is likely to be less tolerant of added stress and to enter an accelerated cycle of death (11) and replication (39). More extensive microthrombosis accompanied by an exaggerated inflammatory response and accelerated death and turnover of the endothelium can be mechanisms for irreversible architectural changes in the microvessels.…”

Section: Discussionmentioning

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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“…20 On the trypsin digest, these acellular capillaries appear as non-perfused naked BM tubes where the endothelial cells have disappeared. 20 Diabetes appears to greatly accelerate the turnover and renewal of retinal microvascular endothelial cells 74 and with prolonged diabetes these cells may exhaust their replicative lifespan as they exceed the so-called Hayflick limit. 75 There is evidence that bone-marrow-derived endothelial progenitor cells could contribute to a compromised endothelial monolayer because these cells are also dysfunctional in diabetes, 76 as is the vessel wall they differentiate onto.…”

Section: Endothelial Cell Death and Acellular Capillary Formationmentioning

confidence: 99%

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

Curtis

Gardiner

Stitt

2009

Eye

318

231

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Retinopathy is a major complication of diabetes mellitus and this condition remains a leading cause of blindness in the working population of developed countries. As diabetic retinopathy progresses a range of neuroglial and microvascular abnormalities develop although it remains unclear how these pathologies relate to each other and their net contribution to retinal damage. From a haemodynamic perspective, evidence suggests that there is an early reduction in retinal perfusion before the onset of diabetic retinopathy followed by a gradual increase in blood flow as the complication progresses. The functional reduction in retinal blood flow observed during early diabetic retinopathy may be additive or synergistic to proinflammatory changes, leucostasis and vasoocclusion and thus be intimately linked to the progressive ischaemic hypoxia and increased blood flow associated with later stages of the disease. In the current review a unifying framework is presented that explains how arteriolar dysfunction and haemodynamic changes may contribute to late stage microvascular pathology and vision loss in human diabetic retinopathy.

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A Morphologic and Autoradiographic Study of Cell Death and Regeneration in the Retinal Microvasculature of Normal and Diabetic Rats

Cited by 80 publications

References 10 publications

Leukocyte-Mediated Endothelial Cell Injury and Death in the Diabetic Retina

Leukocyte-Mediated Endothelial Cell Injury and Death in the Diabetic Retina

Increased Prevalence of Microthromboses in Retinal Capillaries of Diabetic Individuals

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

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