Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor

Published on Feb 27, 2001in Proceedings of the National Academy of Sciences of the United States of America9.412
· DOI :10.1073/PNAS.031252398
Veronica Stellmach16
Estimated H-index: 16
(NU: Northwestern University),
Susan E. Crawford45
Estimated H-index: 45
+ 1 AuthorsNoel P. Bouck51
Estimated H-index: 51
Sources
Abstract
Aberrant blood vessel growth in the retina that underlies the pathology of proliferative diabetic retinopathy and retinopathy of prematurity is the result of the ischemia-driven disruption of the normally antiangiogenic environment of the retina. In this study, we show that a potent inhibitor of angiogenesis found naturally in the normal eye, pigment epithelium-derived growth factor (PEDF), inhibits such aberrant blood vessel growth in a murine model of ischemia-induced retinopathy. Inhibition was proportional to dose and systemic delivery of recombinant protein at daily doses as low as 2.2 mg/kg could prevent aberrant endothelial cells from crossing the inner limiting membrane. PEDF appeared to inhibit angiogenesis by causing apoptosis of activated endothelial cells, because it induced apoptosis in cultured endothelial cells and an 8-fold increase in apoptotic endothelial cells could be detected in situ when the ischemic retinas of PEDF-treated animals were compared with vehicle-treated controls. The ability of low doses of PEDF to curtail aberrant growth of ocular endothelial cells without overt harm to retinal morphology suggests that this natural protein may be beneficial in the treatment of a variety of retinal vasculopathies.
📖 Papers frequently viewed together
315 Citations
1,153 Citations
183 Citations
References52
Newest
#1Takayuki TaniwakiH-Index: 6
#2Naohide Hirashima (NIH: National Institutes of Health)H-Index: 3
Last. Joan P. SchwartzH-Index: 46
view all 6 authors...
Abstract: Pigment epithelium-derived factor (PEDF) is a survival factor for cerebellar granule cells in culture. In the present study, we have investigated the ability of a recombinant form of PEDF (rPEDF) to protect against glutamate neurotoxicity. When rPEDF was added to cerebellar granule cell cultures 30 min before addition of 100 µM glutamate, glutamate-induced neuronal death was significantly reduced. The protective effect of rPEDF was dose-dependent in the range from 0.023 to 7.0 nM (1–50...
160 CitationsSource
#1Afshin Shafiee (Tulane University)H-Index: 1
#2John S. Penn (Vandy: Vanderbilt University)H-Index: 40
Last. Diane A. Blake (Tulane University)H-Index: 27
view all 6 authors...
PURPOSE. Thrombospondin (TSP)-1 is a tumor suppressor with activity that is associated with its ability to inhibit neovascularization. Previous studies have mapped this antiangiogenic activity to the type 1 repeats and the amino-terminal portion of the molecule within the procollagen-like domain. The present study was performed to investigate the ability of TSP-1 and peptides derived from the type 1 repeats to inhibit retinal angiogenesis. METHODS. TSP-1 and peptides with tryptophan-rich, hepari...
98 Citations
#1Tom A. Drixler (UU: Utrecht University)H-Index: 5
#2Inne H.M. Borel Rinkes (UU: Utrecht University)H-Index: 54
Last. Emile E. Voest (UU: Utrecht University)H-Index: 79
view all 6 authors...
Human plasminogen-derived angiostatin is one of the most potent antiangiogenic agents currently known. However, it is unclear whether angiostatin is also effective against accelerated tumor growth induced by local up-regulation of growth factors, including angiogenesis stimulators, such as in regenerating liver. Prior to addressing this question, we tested, in mice, whether continuous administration of angiostatin could improve its biological effects. This assumption was based on the relatively ...
200 Citations
#1Hiroaki Ozaki (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 21
#2Man Seong Seo (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 7
Last. Peter A. Campochiaro (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 121
view all 9 authors...
Retinal vasculogenesis and ischemic retinopathies provide good model systems for study of vascular development and neovascularization (NV), respectively. Vascular endothelial cell growth factor (VEGF) has been implicated in the pathogenesis of retinal vasculogenesis and in the development of retinal NV in ischemic retinopathies. However, insulin-like growth factor-I and possibly other growth factors also participate in the development of retinal NV and intraocular injections of VEGF antagonists ...
495 CitationsSource
#1Nader Sheibani (WashU: Washington University in St. Louis)H-Index: 55
#1Nader Sheibani (WashU: Washington University in St. Louis)H-Index: 31
Last. William A. Frazier (WashU: Washington University in St. Louis)H-Index: 73
view all 4 authors...
Abstract Negative regulators of angiogenesis play a major role in maintaining vascular homeostasis. Thrombospondin-1 (TSP1) is a natural inhibitor of angiogenesis. This report examines the presence of TSP1 in ocular samples and determines whether its production is altered in diabetes. Western blot analysis detected a 140 kDa antiangiogenic fragment of TSP1(gp140) in vitreous samples prepared from normal human and rat eyes. Intact TSP1 was detected in aqueous humor samples prepared from normal ra...
119 CitationsSource
#1Benilde Jiménez (CSIC: Spanish National Research Council)H-Index: 26
#2Olga V. VolpertH-Index: 65
Last. Noel P. Bouck (NU: Northwestern University)H-Index: 51
view all 6 authors...
Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis that limits vessel density in normal tissues and curtails tumor growth. Here, we show that the inhibition of angiogenesis in vitro and in vivo and the induction of apoptosis by thrombospondin-1 all required the sequential activation of CD36, p59fyn, caspase-3 like proteases and p38 mitogen-activated protein kinases. We also detected increased endothelial cell apoptosis in situ at the margins of tumors in mice treated wit...
1,285 CitationsSource
#1Elena M. Alberdi (NIH: National Institutes of Health)H-Index: 4
#2Maria S. Aymerich (NIH: National Institutes of Health)H-Index: 4
Last. S. Patricia Becerra (NIH: National Institutes of Health)H-Index: 30
view all 3 authors...
Abstract Pigment epithelium-derived factor (PEDF) has neuronal differentiation and survival activity on retinoblastoma and cerebellar granule (CG) cells. Here, we investigated the presence of PEDF receptors on retinoblastoma Y-79 and CG cells. PEDF radiolabeled with l25I remained biologically active and was used for radioligand binding analysis. The binding was saturable and specific to a single class of receptors on both cells and with similar affinities (K d = 1.7–3.6 nm, B max = 0.5–2.7 × 105...
111 CitationsSource
#1Lucien J. Houenou (Wake Forest University)H-Index: 26
#2Anselm D’Costa (Wake Forest University)H-Index: 12
Last. S. Patricia Becerra (NIH: National Institutes of Health)H-Index: 30
view all 7 authors...
Pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitor (serpin) superfamily that has been shown previously to promote the survival and/or differentiation of rat cerebellar granule neurons and human retinoblastoma cells in vitro. However, in contrast to most serpins, PEDF has no inhibitory activity against any known proteases, and its described biological activities do not appear to require the serpin-reactive loop located toward the carboxy end of the polypeptide. ...
111 CitationsSource
#1Bharat N Nandgaonkar (GUMC: Georgetown University Medical Center)H-Index: 3
#2Tomas Rotschild (GUMC: Georgetown University Medical Center)H-Index: 3
Last. Rosemary D. Higgins (GUMC: Georgetown University Medical Center)H-Index: 85
view all 4 authors...
Retinopathy of prematurity is a disease commonly affecting extremely premature babies. Indomethacin is widely used in the perinatal period. The goal of the present study was to test the hypothesis that indomethacin will improve retinopathy in a mouse model when administered during the period of injury (hyperoxia exposure) to the developing retinal vasculature. C57BL6 mice pups were exposed to 75% oxygen from postnatal d 7 through 12. Indomethacin was administered along with the oxygen exposure a...
41 CitationsSource
#1David W. Dawson (NU: Northwestern University)H-Index: 43
#2Olga V. Volpert (NU: Northwestern University)H-Index: 65
Last. Noel P. Bouck (NU: Northwestern University)H-Index: 51
view all 7 authors...
In the absence of disease, the vasculature of the mammalian eye is quiescent, in part because of the action of angiogenic inhibitors that prevent vessels from invading the cornea and vitreous. Here, an inhibitor responsible for the avascularity of these ocular compartments is identified as pigment epithelium–derived factor (PEDF), a protein previously shown to have neurotrophic activity. The amount of inhibitory PEDF produced by retinal cells was positively correlated with oxygen concentrations,...
1,248 CitationsSource
Cited By493
Newest
#1Xiaoyan Yang (MOE: Chinese Ministry of Education)H-Index: 7
Background—Atherosclerosis is closely associated with proliferation of the adventitial vasa vasorum, leading to the atherosclerotic plaque progression and vulnerability. In this report, we investigated the role of Ginsenoside Rb1 (Rb1) on atherosclerotic plaque stabi-lization and adventitial vasa vasorum (VV) along with the mechanisms involved. Methods and Results—Apolipoprotein E-deficient (ApoE-/-) mice were fed with a high-fat diet for 20 weeks, and then Ginsenoside Rb1 (50 mg/kg/d, intraperi...
Source
#1Takafumi Tomiyasu (HSUH: Health Sciences University of Hokkaido)H-Index: 1
#2Ayuki Sato (HSUH: Health Sciences University of Hokkaido)
Last. Katsunori Okazaki (HSUH: Health Sciences University of Hokkaido)H-Index: 23
view all 4 authors...
Abstract Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis (EBL) and can be classified into two types based on the amino acid at position 233 in Tax protein, which probably plays crucial roles in leukemogenesis. We previously revealed that L233-Tax-expressing cells secreted chemoattractants for endothelial cells and formed significantly larger tumors accompanying neovascularization than P233-Tax-expressing cells in athymic mice. In the present study, comparative prot...
Source
#1Mehmet Balbaba (Fırat University)H-Index: 3
#2Fatih Ulaş (Abant Izzet Baysal University)H-Index: 8
Last. Suleyman Aydin (Fırat University)H-Index: 39
view all 6 authors...
Purpose:To evaluate the aqueous humor and serum cortistatin levels in diabetic patients with and without diabetic retinopathy and its relationship with various metabolic markers that have been repo...
Source
Source
#1Shu-I Yeh (Mackay Medical College)H-Index: 4
#2Sung-Hsun Yu (NTU: National Taiwan University)H-Index: 1
Last. Wei-Li Chen (NTU: National Taiwan University)H-Index: 22
view all 7 authors...
Purpose To investigate the potential of a pigment epithelium-derived factor (PEDF) peptide 44-mer to promote nerve regeneration in a rabbit corneal nerve injury model to demonstrate its neurotrophic ability in cultivated mouse trigeminal neuron cells. Methods Subconjunctival or intrastromal injection of 44-mer on the cornea was performed in a rabbit model of corneal nerve injury created by corneal epithelial debridement. Immunocytochemical analysis (44-mer, anti-tubulin III, SMI312, CD11b, and α...
Source
Here we discuss antibody, cell and gene-based therapies that are currently available and under investigation for both wet and dry age-related macular degeneration (AMD). We initially discuss ocular anatomy, AMD modelling as well as the underlying pathophysiology of AMD. The antibody-based trials which have revolutionised the management of wet AMD are reviewed. The latest concepts in antibody therapy for wet AMD such as the port delivery systems, bispecific antibodies, designed ankyrin repeat pro...
5 CitationsSource
#1Arina Riabinska (Charité)H-Index: 7
#2Marietta Zille (Charité)H-Index: 15
Last. Ana Luisa Piña (Charité)H-Index: 6
view all 7 authors...
Pigment epithelium-derived factor (PEDF) is a neurotrophic factor with neuroprotective, antiangiogenic, and antipermeability effects. In the brain, blood–brain barrier (BBB) function is essential for homeostasis. Its impairment plays a crucial role in the pathophysiology of many neurological diseases, including ischemic stroke. We investigated (a) whether PEDF counteracted vascular endothelial growth factor (VEGF)-induced BBB disruption in the mouse brain, (b) the time course and route of BBB pe...
3 CitationsSource
#1Xin-Ying Hu (SEU: Southeast University)H-Index: 1
#2Yu-Zhi Ding (SEU: Southeast University)H-Index: 3
Last. Jie Luan (SEU: Southeast University)H-Index: 2
view all 8 authors...
ABSTRACTOBJECTIVE: To investigate the expression of pigment epithelium-derived factor (PEDF) and alphaB-crystallin in human lens epithelial cells (LEC) and explore their relationships with diabetes.METHODS: Lens anterior capsules attached with LEC were collected from cataract surgeries in patients with or without diabetes, and grouped as following: non-diabetes mellitus (NDM) group, no diabetic retinopathy (NDR) group, non-proliferative diabetic retinopathy (NPDR) group and proliferative diabeti...
1 CitationsSource
Choroidal neovascularization (CNV) is a sight-threatening disease and is characterized by the formation of pathological neovascularization in the choroid which extends into the subretinal space. Exudative age-related macular degeneration (AMD) is the formation of CNV in the macular area which leads to irreversible blindness. Continuous leakage and hemorrhage of the CNV lesion may eventually result in scarring or later fibrosis, which could result in photoreceptor cell atrophy. The current strate...
1 CitationsSource
#1Mayss Al-SheikhH-Index: 17
#2Daniel BarthelmesH-Index: 31
Choroidal neovascularization (CNV) is a major cause of severe vision loss in patients with age-related macular degeneration. Despite intensive research, the pathogenesis of choroidal neovascularization is still poorly understood. Many factors were identified to be involved in the development of choroidal neovascularization. Choroidal blood flow and hemodynamic changes with consecutive impairment of the perfusion, especially of the choriocapillaris, as well as reduction of clearance of debris fro...
Source