Localization of Vascular Endothelial Growth Factor in Human Retina and Choroid

Lutty, Gerard A.; McLeod, D. Scott; Merges, Carol; Diggs, Annia; Plouët, Jean

doi:10.1001/archopht.1996.01100140179011

Cited by 234 publications

(130 citation statements)

References 31 publications

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“…Moreover, VEGF, as an angiogenesis inducer, plays a pivotal role in DR and is implicated as the initiator and mediator of nonproliferative and proliferative DRs. 42,43 Repeated injections of high concentrations of VEGF in eyes of nondiabetic monkeys provoke retinal changes that resemble those observed in the early stages of DR, including vascular tortuosity and microaneurysms. 44,45 Clinical trials using anti-VEGF therapies are showing promising results against advanced stages of DR. 46,47 Thus, without excluding the activation of other transduction pathways associated with retinal IPC, such as adenosine, K ATP channels, protein kinase C, 12,48 -49 and NO, 50 among others, and based on the fact that ischemia pulses abrogated the increase in VEGF, it is tempting to speculate that the induction of ischemic conditioning could behave as an anti-VEGF therapy.…”

Section: Discussionmentioning

confidence: 99%

Induction of Ischemic Tolerance Protects the Retina From Diabetic Retinopathy

Fernandez

Sande

Chianelli

et al. 2011

The American Journal of Pathology

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Diabetic retinopathy is a leading cause of acquired blindness. Available treatments are not very effective. We investigated the effect of a weekly application of retinal ischemia pulses (ischemic conditioning) on retinal damage induced by experimental diabetes. Diabetes was induced by an intraperitoneal injection of streptozotocin. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 minutes; this maneuver started 3 days after streptozotocin injection and was weekly repeated in one eye, whereas the contralateral eye was submitted to a sham procedure. Diabetic retinopathy was evaluated in terms of i) retinal function (electroretinogram and oscillatory potentials), ii) integrity of blood-retinal barrier (by albumin-Evans blue complex leakage and astrocyte glial fibrillary acidic protein IHC), iii) optical and electron microscopy histopathologic studies, and iv) vascular endothelial growth factor levels (using Western blot analysis and IHC). Brief ischemia pulses significantly preserved electroretinogram a-and b-wave and oscillatory potentials, avoided albumin-Evans blue leakage, prevented the decrease in astrocyte glial fibrillary acidic protein levels, reduced the appearance of retinal edemas, and prevented the increase in vascular endothelial growth factor levels induced by experimental diabetes. When the application of ischemia pulses started 6 weeks after diabetes onset, retinal function was significantly preserved. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies for diabetic retinopathy treatment.

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Section: Discussionmentioning

confidence: 99%

Induction of Ischemic Tolerance Protects the Retina From Diabetic Retinopathy

Fernandez

Sande

Chianelli

et al. 2011

The American Journal of Pathology

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“…Vascular hypertrophy and angiogenesis also have been associated with diabetes, albeit only in selected organs (Lutty et al, 1996;Norrby et al, 1990a;Vranes et al, 1995a). This abnormal endothelial proliferation is at present explained by the expression, at the affected site, of endothelial growth factors, particularly the vascular endothelial growth factor (VEGF CentreVille, Montréal, Québec, H3C 3J7,.ca 0023-6837/00/8008-1171$03.00/0 LABORATORY INVESTIGATION Vol.…”

Section: Discussionmentioning

confidence: 99%

Alterations of the Rat Mesentery Vasculature in Experimental Diabetes

Arshi

Bendayan

Ghitescu

2000

Laboratory Investigation

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SUMMARY:The alteration induced by diabetes on vascular permeability to serum albumin was investigated in the mesentery of streptozotocin-induced hyperglycemic rats. Double-tagged ( 125 I and dinitrophenol-haptenated) heterologous albumin was intravenously administered in normal and hyperglycemic animals, and the extravasation of the tracer was evaluated by radioactivity measurements and by morphometry at the ultrastructural level using quantitative protein A-colloidal gold immunocytochemistry. The results demonstrate that diabetes induces a significant increase in the permeability of the mesentery vessels to albumin. This increase is due to a more efficient transport of macromolecules by endothelial plasmalemmal vesicles and not to leakier interendothelial junctions. Passage across the endothelial basement membranes did not appear to be restricted in either the control or diabetic condition. However, in diabetes, the mesothelial basement membrane appeared to become modified and to restrain the passage of albumin toward the peritoneal cavity. After 3 months of diabetes, the rats presented a net increase in the average diameter of the blood vessels localized in the mesentery arcada (macrovascular hyperplasy) and a notable angiogenesis, manifested at the level of the microvasculature in the mesenteric windows. (Lab Invest 2000, 80:1171-1184.T he association of diabetes with vascular dysfunctions gradually evolving toward incapacitating or life-threatening vascular pathologies is undisputed. Extensive clinical observations and studies on animal models have amply documented that hyperglycemia accelerates and worsens atherosclerosis in large arteries (Colwell et al, 1988;Shantaram, 1999;Steiner 1997) and affects, although in different ways, the microvessels of selected vascular beds, such as those of the retina (Bazan et al, 1997;Cunha-Vaz, 1983;Porta, 1996;Ruggiero et al, 1997), kidney (Flyvbjerg, 1997;Mauer et al, 1984;Nyengaard and Bendtsen, 1993;Vlassara et al, 1994), and nerves (Cameron and Cotter, 1997;Malik et al, 1993; Tesfay et al, 1994). Particular attention has been directed to the study of diabetes-induced retinopathies and nephropathies, because of their obvious clinical implications. On the other hand, the impact of diabetes on other vascular beds has been generally overlooked. Therefore, it is not known whether diabetic microangiopathy concerns all blood vessels, creating a sort of "dysfunctional background" exacerbated in particular tissues by local factors to a full blown vascular pathology, or the vasculature of many organs is simply spared by the deleterious effects of hyperglycemia/ hypoinsulinemia. The latter hypothesis would fall in line with the ever-growing body of evidence pointing to important physiological and biochemical dissimilarities between various vascular segments (Boegehold, 1998;Rajotte et al, 1998;Thorin and Shreeve, 1998).Several morphologic features and physiologic parameters appear as leit motifs of diabetic microangiopathies. Among these, the thickening of the basement membran...

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“…In the diabetic GK rats, strong VEGF immunoreactivity was also associated with the choroid, whereas only weak or no choroidal VEGF distribution was observed in control Wistar rats. Recently reported immunohistochemical VEGF localization on postmortem human eyes with and without diabetes showed that VEGF immunoreactivity in the choroid was almost exclusively found in patients with diabetes [10]. The implication(s) of choroid derived VEGF in the pathophysiology of diabetic retinopathy and other ocular complications are not well understood.…”

Section: Discussionmentioning

confidence: 99%