Angiostatic Effect of Penetrating Ocular Injury: Role of Pigment Epithelium-Derived Factor (original) (raw)
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Molecular vision, 2004
Perforation injury to the eye can protect against retinal degeneration and pigment epithelial derived factor (PEDF) may play a role in this neuro-protective effect. PEDF has also been shown to possess potent anti-angiogenic properties. The current study has investigated a possible anti-angiogenic effect of penetrating ocular injury in a murine model of oxygen induced proliferative retinopathy (OIR) and determined if such a procedure alters PEDF expression in the retina. OIR was produced by exposure of neonatal mice to 75% oxygen between postnatal days 7 and 12 (P7-P12). Mice were separated into various groups, with one group receiving a penetrating injury in a single eye. Pre-retinal neovascularization and intra-retinal ischaemia was quantified at P17 and PEDF protein expression was determined using immunofluorescence in retinal flatmounts and sections. PEDF mRNA was quantified using real-time RT-PCR. Punctured eyes showed less pre-retinal neovascularization at P17 when compared to ...
Oxidative Medicine and Cellular Longevity
Ocular ischemia/hypoxia is a severe problem in ophthalmology that can cause vision impairment and blindness. However, little is known about the changes occurring in the existing fully formed choroidal blood vessels. We developed a new whole organ culture model for ischemia/hypoxia in rat eyes and investigate the effects of pigment epithelium derived factor (PEDF) protein on the eye tissues. The concentration of oxygen within the vitreous was measured in the enucleated rat eyes and living rats. Then, ischemia was mimicked by incubating the freshly enucleated eyes in medium at 4°C for 14 h. Eyes were fixed immediately after enucleation or were intravitreally injected with PEDF protein or with vehicle before incubation. After incubation, light and electron microscopy (EM) as well as Tunel staining was performed. In the living rats, the intravitreal oxygen concentration was on average at 16.4% of the oxygen concentration in the air and did not change throughout the experiment whereas it...
The Role of Intravitreal Anti-VEGF Agents in Rabbit Eye Model of Open-Globe Injury
Journal of Ophthalmology, 2021
Purpose To evaluate the effects of intravitreal anti-VEGF agents in a rabbit model of open-globe injury (OGI). Methods OGI was induced in the right eyes of 75 Belgian rabbits by making 5 mm circumferential incision placed 6 mm behind the limbus. The rabbits were divided into 4 groups: control (n = 5), OGI group (n = 40), and intravitreal Ranibizumab and Conbercept (n = 15 each). Ranibizumab or Conbercept was injected into the vitreous at 0.5 hours, 3 days, or 7 days. Vitreous fluid was collected, and levels of growth factors and cytokines were measured by enzyme-linked immunosorbent assay (ELISA). On day 28 after OGI, B scan examination and histological examination were performed to evaluate intravitreal proliferation and formation of epiretinal fibrosis. Results Vitreous levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and plasminogen activator inhibitor-1 (PAI-1) were significantly increased in rab...
Vascular endothelial growth factor in aqueous humor of patients with perforative eye injuries
Coll. Antropol, 2008
During the surgery, aqueous humor samples were taken out and VEGF levels were measured by ELISA. VEGF levels were significantly higher in the aqueous humor of patients with open globe eye injury and uveitis, in patients with wound bigger than 2 mm and in patients where from injury to surgery passed more than 4 hours. VEGF levels were also higher, but not significantly, in patients with intrabulbar foreign body. Considering that VEGF levels were significantly higher in patients with open globe eye injury with uveitis, wound larger than 2 mm and in patients where from injury to surgery passed more than 4 hours, anti VEGF therapy might have application in these conditions.
Experimental Eye Research, 2020
Retinopathy of prematurity (ROP) is a growing cause of lifelong blindness and visual defects as improved neonatal care worldwide increases survival in very-low-birthweight preterm newborns. Advancing ROP is managed by laser surgery or a single intravitreal injection of anti-VEGF, typically at 33-36 weeks gestational age. While newer methods of scanning and telemedicine improve monitoring ROP, the above interventions are more difficult to deliver in developing countries. There is also concern as to laser-induced detachment and adverse developmental effects in newborns of anti-VEGF treatment, spurring a search for alternative means of mitigating ROP. Pigment epithelium-derived factor (PEDF), a potent angiogenesis inhibitor appears late in gestation, is undetected in 25-28 week vitreous, but present at full term. Its absence may contribute to ROP upon transition from high-to-ambient oxygen environment or with intermittent hypoxia. We recently described antiangiogenic PEDF-derived small peptides which inhibit choroidal neovascularization, and suggested that their target may be laminin receptor, 67LR. The latter has been implicated in oxygen-induced ischemic retinopathy (OIR). Here we examined the effect of a nonapeptide, PEDF 336, in a newborn mouse OIR model. Neovascularization was significantly decreased in a dose-responsive manner by single intravitreal (IVT) injections of 1.25-7.5 μg/eye (1.0-6.0 nmol/eye). By contrast, anti-mouse VEGFA 164 was only effective at 25 ng/eye, with limited dose-response. Combination of anti-VEGFA 164 with PEDF 336 gave only the poorer anti-VEGF response while abrogating the robust inhibition seen with peptide-alone, suggesting a need for VEGF in sensitizing the endothelium to the peptide. VEGF stimulated 67LR presentation on endothelial cells, which was decreased in the presence of PEDF 336. Mouse and rabbit eyes showed no histopathology or inflammation after IVT peptide injection. Thus, PEDF 336 is a potential ROP therapeutic, but is not expected to be beneficial in combination with anti-VEGF.
Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization
Journal of Cellular Physiology, 2001
In this study, we investigated whether overexpression of pigment epitheliumderived factor (PEDF) by gene transfer can inhibit neovascularization by testing its effect in three different models of ocular neovascularization. Intravitreous injection of an adenoviral vector encoding PEDF resulted in expression of PEDF mRNA in the eye measured by RT-PCR and increased immunohistochemical staining for PEDF protein throughout the retina. In mice with laser-induced rupture of Bruch's membrane, choroidal neovascularization was signi®cantly reduced after intravitreous injection of PEDF vector compared to injection of null vector or no injection. Subretinal injection of the PEDF vector resulted in prominent staining for PEDF in retinal pigmented epithelial cells and strong inhibition of choroidal neovascularization. In two models of retinal neovascularization (transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors and mice with oxygen-induced ischemic retinopathy), intravitreous injection of null vector resulted in decreased neovascularization compared to no injection, but intravitreous injection of PEDF vector resulted in further inhibition of neovascularization that was statistically signi®cant. These data suggest that sustained increased intraocular expression of PEDF by gene therapy might provide a promising approach for treatment of ocular neovascularization.
Investigative Ophthalmology & Visual Science, 2003
PURPOSE. To determine whether intraocular gene transfer of pigment epithelium-derived factor (PEDF) protects the retina from ischemia-reperfusion injury. METHODS. Four days before induction of pressure-induced ischemia, Lewis rats received intravitreous injection of 3 ϫ 10 9 particles of an adenovirus vector expressing PEDF (AdPEDF.11) in one eye and 3 ϫ 10 9 particles of an empty adenovirus vector (AdNull.11) in the contralateral eye. Seven days after reperfusion, eyes were enucleated and processed for morphometric analysis. Apoptotic cells stained by TdT-dUTP terminal nick-end labeling (TUNEL) in the retina were counted 12 hours after initiation of reperfusion. Retina levels of PEDF were measured by enzyme-linked immunosorbent assay. RESULTS. PEDF levels in retinal homogenates from eyes receiving AdPEDF.11 injection were well above the background levels in the untreated baseline and control eyes (P ϭ 0.04). Retinal thickness was preserved in AdPEDF.11-treated eyes. Retinal cell density was significantly greater in the ganglion cell layer (GCL; P ϭ 0.014), inner nuclear layer (INL; P ϭ 0.008), and outer nuclear layer (ONL; P ϭ 0.008) of AdPEDF.11-treated eyes compared with the corresponding layers in AdNull.11-treated eyes. AdNull.11treated eyes also had significantly more TUNEL-positive cells in these layers than AdPEDF.11-treated eyes (P Ͻ 0.05). CONCLUSIONS. Adenoviral vector-mediated intraocular expression of PEDF significantly increases cell survival after ischemiareperfusion injury of the retina. The protective effect may result from inhibition of ischemia-induced apoptosis. This study provides proof of concept for a gene transfer approach directed at interrupting programmed cell death induced by retinal ischemic insult.