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Reinier O Schlingemann - One of the best experts on this subject based on the ideXlab platform.
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altered expression patterns of vegf receptors in human diabetic retina and in Experimental vegf induced retinopathy in Monkey
Investigative Ophthalmology & Visual Science, 2002Co-Authors: A N Witmer, H G T Blaauwgeers, Herbert A Weich, Kari Alitalo, Gijs F J M Vrensen, Reinier O SchlingemannAbstract:PURPOSE. The vascular endothelial growth factor (VEGF) family is involved in vascular leakage and angiogenesis in diabetic retinopathy (DR) in the eye, but may also have physiological functions. Based on the hypothesis that differential VEGF receptor (VEGFR) expression in the retina is an important determinant of effects of VEGF, this study was conducted to investigate VEGFR expression in the diabetic retina and in an Experimental Monkey model of VEGF-A–induced retinopathy. METHODS. In retinas of 27 eyes of diabetic donors, 18 eyes of nondiabetic control donors, and 4 Monkey eyes injected with PBS or VEGF-A, expression patterns of VEGFR-1, -2, and -3 in relation to leaky microvessels, as identified by the marker pathologische anatomie Leiden-endothelium (PAL-E) were studied by immunohistochemistry. RESULTS. In control human retinas and retinas of PBS-injected Monkey eyes, all three VEGFRs were expressed in nonvascular areas, but only VEGFR-1 was constitutively expressed in retinal microvessels. In diabetic eyes, increased microvascular VEGFR-2 expression was found in association with PAL-E expression, whereas microvascular VEGFR-3 was present in a subset of PAL-E–positive cases. In VEGF-A–injected Monkey eyes, VEGFR-1, -2, and -3 and PAL-E were expressed in retinal microvessels. CONCLUSIONS. The VEGFR-1, -2, and -3 expression patterns in control retinas suggest physiological functions of VEGFs that do not involve the vasculature. Initial vascular VEGF signaling may act primarily through VEGFR-1. In diabetic eyes, expression of retinal VEGFR-2 and -3 is increased, mainly in leaky microvessels, and VEGF-A induces vascular expression of the VEGF-A receptor VEGFR-2 and the VEGF-C/D receptor VEGFR-3. These findings indicate a dual role of VEGFs in the physiology and pathophysiology of the retina and suggest that microvascular VEGFR-2 and -3 signaling by VEGFs occurs late in the pathogenesis of DR, possibly initiated by high levels of VEGF-A in established nonproliferative DR. (Invest Ophthalmol Vis Sci. 2002;43:849 – 857)
John C Morrison - One of the best experts on this subject based on the ideXlab platform.
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global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model
Investigative Ophthalmology & Visual Science, 2007Co-Authors: Elaine C Johnson, L Jia, William O Cepurna, Thomas A Doser, John C MorrisonAbstract:Glaucoma is the second leading cause of blindness worldwide, affecting approximately 60 million people.1 Although many risk factors are associated with glaucoma, IOP is the most widely recognized, and lowering IOP is the goal of current glaucoma therapies. When IOP is Experimentally elevated in nonhuman primates, the pattern of optic nerve head (ONH) cupping, optic nerve axon degeneration, and selective loss of retinal ganglion cells replicates the pathologic features of human glaucoma. Clinically, human glaucomatous optic neuropathy is characterized by optic disc cupping and a pattern of visual field loss.2 Cupping results from the loss of optic nerve axons and posterior bowing and remodeling of the support structures of the ONH.3,4 Often, these changes are most pronounced in the superior and inferior parts of the nerve head. The most characteristic visual field defect is the arcuate scotoma, which arches above or below central fixation and follows the pathways of the nerve fiber bundles as they converge on the superior and inferior poles of the ONH.2,5,6 Regional variation in laminar structure suggests less support and protection for axons, possibly explaining the apparent increased susceptibility of axons that pass through the superior and inferior ONH. In the face of increased or fluctuating IOP, movement of the lamina may result in preferential mechanical injury to neural tissues in these regions.7 In addition, because the vascular supply to the ONH tissue lies within the laminar beams, this pattern could result in regionally compromised blood flow.8 Current Experimental evidence supporting either of these mechanisms is limited, and the cellular events that connect the regional pattern of glaucomatous optic nerve damage with the known structural anatomy of the ONH are still largely unknown. Regardless of mechanism, the variation in the structure of the ONH provides the only anatomic correlation with the characteristic pattern of glaucomatous optic nerve axon loss. The apparent vulnerability of the ONH to pressure-induced axonal injury has led many investigators to examine changes in the composition of glaucomatous human and Experimental Monkey ONH tissues. These ONHs are characterized by axon loss, gliotic scaring, increased expression of matrix metalloproteinases, and abnormal deposition of extracellular matrix (ECM) materials, including collagens, tropoelastin, tenascin, and proteoglycans.9–20 In the rat, glaucoma can be modeled by sclerosing aqueous outflow pathways to produce a sustained elevation of IOP.21 In this model, pressure causes a selective loss of retinal ganglion cells and a characteristic pattern of axon degeneration that begins in the superior quadrant of the optic nerve.21,22 In addition, immunohistochemical studies of ONH reveal that pressure-induced injury is accompanied by deposition of collagens and other ECM components, similar to that in human glaucoma.23 This deposition of ECM is preceded by a loss of gap junctional connexin 43 immunolabeling and evidence of astrocytic proliferation.24 By immunohistochemical analysis, the initial evidence of ECM deposition coincided with a decrease in ONH labeling for neurotrophins and astrocytic GFAP.24 Although the ONH is recognized as the likely site of initial injury in human glaucoma and in Experimental IOP elevation glaucoma models, very little is known about the changes in gene expression that accompany this injury. In this study, we used microarray analysis to identify the genes and functional gene classes most altered in expression in the rat ONH after exposure to Experimentally elevated pressure that results in extensive and ongoing optic nerve degeneration. Then, we used real-time quantitative (q)PCR to verify selected changes in gene expression initially identified by microarray analysis and to examine several genes not included on the arrays. To expand this study, we included qPCR analyses of ONHs from eyes with focal regions of degeneration in optic nerve cross-sections. Focal injury occurs in eyes with more mild pressure elevations or those of shorter duration and probably reflects earlier responses to pressure-induced nerve injury. We compared injury in these ONHs to those in ONHs with more extensive injury due to elevated IOP and to those after optic nerve transection, to evaluate ONH responses to simple loss of axons. The expansion of the qPCR study to nerves with focal injuries allows us to explore the potential of discovering, by future microarray analyses, unique or more dramatic alterations in gene expression that occur early in the injury process. To our knowledge, this is the first genome-wide analysis of expression changes in the ONH in response to elevated IOP.
A N Witmer - One of the best experts on this subject based on the ideXlab platform.
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altered expression patterns of vegf receptors in human diabetic retina and in Experimental vegf induced retinopathy in Monkey
Investigative Ophthalmology & Visual Science, 2002Co-Authors: A N Witmer, H G T Blaauwgeers, Herbert A Weich, Kari Alitalo, Gijs F J M Vrensen, Reinier O SchlingemannAbstract:PURPOSE. The vascular endothelial growth factor (VEGF) family is involved in vascular leakage and angiogenesis in diabetic retinopathy (DR) in the eye, but may also have physiological functions. Based on the hypothesis that differential VEGF receptor (VEGFR) expression in the retina is an important determinant of effects of VEGF, this study was conducted to investigate VEGFR expression in the diabetic retina and in an Experimental Monkey model of VEGF-A–induced retinopathy. METHODS. In retinas of 27 eyes of diabetic donors, 18 eyes of nondiabetic control donors, and 4 Monkey eyes injected with PBS or VEGF-A, expression patterns of VEGFR-1, -2, and -3 in relation to leaky microvessels, as identified by the marker pathologische anatomie Leiden-endothelium (PAL-E) were studied by immunohistochemistry. RESULTS. In control human retinas and retinas of PBS-injected Monkey eyes, all three VEGFRs were expressed in nonvascular areas, but only VEGFR-1 was constitutively expressed in retinal microvessels. In diabetic eyes, increased microvascular VEGFR-2 expression was found in association with PAL-E expression, whereas microvascular VEGFR-3 was present in a subset of PAL-E–positive cases. In VEGF-A–injected Monkey eyes, VEGFR-1, -2, and -3 and PAL-E were expressed in retinal microvessels. CONCLUSIONS. The VEGFR-1, -2, and -3 expression patterns in control retinas suggest physiological functions of VEGFs that do not involve the vasculature. Initial vascular VEGF signaling may act primarily through VEGFR-1. In diabetic eyes, expression of retinal VEGFR-2 and -3 is increased, mainly in leaky microvessels, and VEGF-A induces vascular expression of the VEGF-A receptor VEGFR-2 and the VEGF-C/D receptor VEGFR-3. These findings indicate a dual role of VEGFs in the physiology and pathophysiology of the retina and suggest that microvascular VEGFR-2 and -3 signaling by VEGFs occurs late in the pathogenesis of DR, possibly initiated by high levels of VEGF-A in established nonproliferative DR. (Invest Ophthalmol Vis Sci. 2002;43:849 – 857)
Goji Tomita - One of the best experts on this subject based on the ideXlab platform.
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movement of retinal vessels toward the optic nerve head after increasing intraocular pressure in Monkey eyes with Experimental glaucoma
Experimental Eye Research, 2017Co-Authors: Atsumi Kuroda, Nobuko Enomoto, Kyoko Ishida, Masamitsu Shimazawa, Tetsuro Noguchi, Naoto Horai, Hirotaka Onoe, Hideaki Hara, Goji TomitaAbstract:Abstract A shift or displacement of the retinal blood vessels (RBVs) with neuroretinal rim thinning indicates the progression of glaucomatous optic neuropathy. In chronic open angle glaucoma, individuals with RBV positional shifts exhibit more rapid visual field loss than those without RBV shifts. The retinal vessels reportedly move onto the optic nerve head (ONH) in response to glaucoma damage, suggesting that RBVs are pulled toward the ONH in response to increased cupping. Whether this phenomenon only applies to RVBs located in the vicinity or inside the ONH or, more generally, to RBVs also located far from the ONH, however, is unclear. The aim of this study was to evaluate the movement of RBVs located relatively far from the ONH edge after increasing intraocular pressure (IOP) in an Experimental Monkey model of glaucoma. Fundus photographs were obtained in 17 Monkeys. High IOP was induced in the Monkeys by laser photocoagulation burns applied uniformly with 360° irradiation around the trabecular meshwork of the left eye. The right eye was left intact and used as a non-treated control. Considering the circadian rhythm of IOP, it was measured in both eyes of each animal at around the same time-points. Then, fundus photographs were obtained. Using Image J image analysis software, an examiner (N.E.) measured the fundus photographs at two time-points, i.e. before laser treatment (time 1) and the last fundus photography after IOP elevation (time 2). The following parameters were measured (in pixels): 1) vertical diameter of the ONH (DD), 2) distance from the ONH edge to the first bifurcation point of the superior branch of the central retinal vein (UV), 3) distance from the ONH edge to the first bifurcation point of the inferior branch of the central retinal vein (LV), 4) ONH area, and 5) surface area of the cup of the ONH. We calculated the ratios of UV to DD (UV/DD), LV to DD (LV/DD), and the cup area to disc area ratio (C/D). The mean UV/DD at time 1 (0.656 ± 0.233) was decreased at time 2 (0.542 ± 0.192) (p Therefore, in an Experimental Monkey model of glaucoma, RBVs located relatively far from the ONH were pulled toward the ONH as cupping increased.
Elaine C Johnson - One of the best experts on this subject based on the ideXlab platform.
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global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model
Investigative Ophthalmology & Visual Science, 2007Co-Authors: Elaine C Johnson, L Jia, William O Cepurna, Thomas A Doser, John C MorrisonAbstract:Glaucoma is the second leading cause of blindness worldwide, affecting approximately 60 million people.1 Although many risk factors are associated with glaucoma, IOP is the most widely recognized, and lowering IOP is the goal of current glaucoma therapies. When IOP is Experimentally elevated in nonhuman primates, the pattern of optic nerve head (ONH) cupping, optic nerve axon degeneration, and selective loss of retinal ganglion cells replicates the pathologic features of human glaucoma. Clinically, human glaucomatous optic neuropathy is characterized by optic disc cupping and a pattern of visual field loss.2 Cupping results from the loss of optic nerve axons and posterior bowing and remodeling of the support structures of the ONH.3,4 Often, these changes are most pronounced in the superior and inferior parts of the nerve head. The most characteristic visual field defect is the arcuate scotoma, which arches above or below central fixation and follows the pathways of the nerve fiber bundles as they converge on the superior and inferior poles of the ONH.2,5,6 Regional variation in laminar structure suggests less support and protection for axons, possibly explaining the apparent increased susceptibility of axons that pass through the superior and inferior ONH. In the face of increased or fluctuating IOP, movement of the lamina may result in preferential mechanical injury to neural tissues in these regions.7 In addition, because the vascular supply to the ONH tissue lies within the laminar beams, this pattern could result in regionally compromised blood flow.8 Current Experimental evidence supporting either of these mechanisms is limited, and the cellular events that connect the regional pattern of glaucomatous optic nerve damage with the known structural anatomy of the ONH are still largely unknown. Regardless of mechanism, the variation in the structure of the ONH provides the only anatomic correlation with the characteristic pattern of glaucomatous optic nerve axon loss. The apparent vulnerability of the ONH to pressure-induced axonal injury has led many investigators to examine changes in the composition of glaucomatous human and Experimental Monkey ONH tissues. These ONHs are characterized by axon loss, gliotic scaring, increased expression of matrix metalloproteinases, and abnormal deposition of extracellular matrix (ECM) materials, including collagens, tropoelastin, tenascin, and proteoglycans.9–20 In the rat, glaucoma can be modeled by sclerosing aqueous outflow pathways to produce a sustained elevation of IOP.21 In this model, pressure causes a selective loss of retinal ganglion cells and a characteristic pattern of axon degeneration that begins in the superior quadrant of the optic nerve.21,22 In addition, immunohistochemical studies of ONH reveal that pressure-induced injury is accompanied by deposition of collagens and other ECM components, similar to that in human glaucoma.23 This deposition of ECM is preceded by a loss of gap junctional connexin 43 immunolabeling and evidence of astrocytic proliferation.24 By immunohistochemical analysis, the initial evidence of ECM deposition coincided with a decrease in ONH labeling for neurotrophins and astrocytic GFAP.24 Although the ONH is recognized as the likely site of initial injury in human glaucoma and in Experimental IOP elevation glaucoma models, very little is known about the changes in gene expression that accompany this injury. In this study, we used microarray analysis to identify the genes and functional gene classes most altered in expression in the rat ONH after exposure to Experimentally elevated pressure that results in extensive and ongoing optic nerve degeneration. Then, we used real-time quantitative (q)PCR to verify selected changes in gene expression initially identified by microarray analysis and to examine several genes not included on the arrays. To expand this study, we included qPCR analyses of ONHs from eyes with focal regions of degeneration in optic nerve cross-sections. Focal injury occurs in eyes with more mild pressure elevations or those of shorter duration and probably reflects earlier responses to pressure-induced nerve injury. We compared injury in these ONHs to those in ONHs with more extensive injury due to elevated IOP and to those after optic nerve transection, to evaluate ONH responses to simple loss of axons. The expansion of the qPCR study to nerves with focal injuries allows us to explore the potential of discovering, by future microarray analyses, unique or more dramatic alterations in gene expression that occur early in the injury process. To our knowledge, this is the first genome-wide analysis of expression changes in the ONH in response to elevated IOP.
