Abstract
ObjectiveThere are controversies regarding the pro-angiogenic activity of placental growth factor (PGF) in diabetic retinopathy (DR). For a better understanding of its role on the retina, we have evaluated the effect of a sustained PGF over-expression in rat ocular media, using ciliary muscle electrotransfer (ET) of a plasmid encoding rat PGF-1 (pVAX2-rPGF-1).Materials and MethodspVAX2-rPGF-1 ET in the ciliary muscle (200 V/cm) was achieved in non diabetic and diabetic rat eyes. Control eyes received saline or naked plasmid ET. Clinical follow up was carried out over three months using slit lamp examination and fluorescein angiography. After the control of rPGF-1 expression, PGF-induced effects on retinal vasculature and on the blood-external barrier were evaluated respectively by lectin and occludin staining on flat-mounts. Ocular structures were visualized through histological analysis.ResultsAfter fifteen days of rPGF-1 over-expression in normal eyes, tortuous and dilated capillaries were observed. At one month, microaneurysms and moderate vascular sprouts were detected in mid retinal periphery in vivo and on retinal flat-mounts. At later stages, retinal pigmented epithelial cells demonstrated morphological abnormalities and junction ruptures. In diabetic retinas, PGF expression rose between 2 and 5 months, and, one month after ET, rPGF-1 over-expression induced glial activation and proliferation.ConclusionThis is the first demonstration that sustained intraocular PGF production induces vascular and retinal changes similar to those observed in the early stages of diabetic retinopathy. PGF and its receptor Flt-1 may therefore be looked upon as a potential regulatory target at this stage of the disease.
Highlights
Pathogenic events in diabetic retinopathy (DR) include capillary basement membrane thickening, loss of microvascular intramural pericytes and leaky dilation [1,2]
placental growth factor (PGF) expression rose between 2 and 5 months, and, one month after ET, rat PGF-1 (rPGF-1) over-expression induced glial activation and proliferation. This is the first demonstration that sustained intraocular PGF production induces vascular and retinal changes similar to those observed in the early stages of diabetic retinopathy
Since its discovery in ocular fluids from patients with proliferative diabetic retinopathy (PDR) [3,4], VEGF has been recognized as a major pro angiogenic factor produced in response to hyperglycaemia and ischemia
Summary
Pathogenic events in diabetic retinopathy (DR) include capillary basement membrane thickening, loss of microvascular intramural pericytes and leaky dilation [1,2]. Capillary occlusion induces retinal ischemia and subsequent retinovitreal neovascularization causing bleeding and traction retinal detachments. Since its discovery in ocular fluids from patients with proliferative diabetic retinopathy (PDR) [3,4], VEGF has been recognized as a major pro angiogenic factor produced in response to hyperglycaemia and ischemia. The retinopathy of prematurity model is commonly used to study ischemic-related retinal diseases [6,7]. Whilst VEGF blockade has been demonstrated to efficiently reduce neovascularization progression and leakage in age-related macular degeneration, its exact place in the management of DR remains to be clarified. The effectiveness of anti VEGF therapies in patients with diabetic macular edema remains disputable [15] and suggests that other hypoxia-induced molecular factors may be involved such as PDGF, IGF-1, HGF, bFGF/FGF2 [16]. Placental growth factor (PGF) found at high levels in the vitreous [17,18,19] and the retina [20] of diabetic patients may have particular interest
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