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PubMed2002

Effects of angiogenic growth factor combinations on retinal endothelial cells.

The aim of this paper was to determine if growth factors, known to be upregulated in proliferative diabetic retinopathy, exerted combined effects on retinal endothelial cells. The authors explored the individual and collective actions of insulin-like growth factor I (IGF-I), vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), fibroblast growth factor-2 (FGF-2) and placenta growth factor (PlGF) on several parameters that reflect the angiogenic potential of endothelial cells. The effect of growth factors on cell migration and survival/proliferation was examined using primary cultures of bovine retinal endothelial cells (BREC). The authors also determined the growth factor action on capillary-like tube formation on a reconstituted basement membrane matrix and on the newly described phenomenon of secondary sprouting, in which endothelial cell colonies spontaneously survive, proliferate, migrate and invade the matrix after the original capillary-like tubes have collapsed. Sprouting cells were positive for von Willebrand factor and could aggregate into larger tubes with lumens. Incubation with VEGF+IGF-I or PlGF+FGF-2 enhanced tube stability by 40-50%, more than each growth factor alone or other combinations (5-20%). The concurrent addition of four growth factors did not improve the response seen with growth factor pairs. Surprisingly, PDGF-BB induced tube collapse. IGF-I and FGF-2 mildly enhanced BREC proliferation/survival (5-15%). However, VEGF+IGF-I or PlGF+FGF-2 increased BREC proliferation/survival by 25% under low serum conditions, whereas combinations of all four growth factors exerted a clearly synergistic effect (250% increase). PDGF-BB or FGF-2 stimulated secondary sprouting and were the only factors capable of exerting this effect alone. Even though VEGF, IGF-I or PlGF were not effective, if administered in pairs, they demonstrated increased responses. PDGF-BB was also able to enhance the effect of FGF-2+IGF-I+VEGF on BREC secondary sprouting, but not of any of them individually. No other growth factor tested was able to significantly improve the action of combinations of three other growth factors. VEGF increased cell migration in a wounded monolayer assay two-fold and PDGF-BB, 2.5 times, but other individual growth factors were ineffective. PlGF+FGF-2 enhanced cell migration more than each factor alone. VEGF+IGF-I+PlGF+FGF-2, however, increased cell migration four-fold. In summary, this study indicates that growth factors, overexpressed in diabetic retinopathy eyes, enhance the angiogenic characteristics of cultured cells (tube formation, proliferation, secondary sprouting and migration). Their effects, however, can be greatly augmented by other growth factors that alone exert little or no action. Therefore, diabetic retinal neovascularization may result from the additive or synergistic action of several growth factors.

Angiogenesis Inducing Agents↗
PubMed1998

Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity.

Angiogenesis depends on both cell adhesion and proteolytic mechanisms. In fact, matrix metalloproteinase 2 (MMP-2) and integrin alphavbeta3 are functionally associated on the surface of angiogenic blood vessels. A fragment of MMP-2, which comprises the C-terminal hemopexin-like domain, termed PEX, prevents this enzyme binding to alphavbeta3 and blocks cell surface collagenolytic activity. PEX blocks MMP-2 activity on the chick chorioallantoic membrane where it disrupts angiogenesis and tumor growth. Importantly, a naturally occurring form of PEX can be detected in vivo in conjunction with alphavbeta3 expression in tumors and during developmental retinal neovascularization. Levels of PEX in these vascularized tissues suggest that it interacts with endothelial cell alphavbeta3 where it serves as a natural inhibitor of MMP-2 activity, thereby regulating the invasive behavior of new blood vessels.

Allantois↗
PubMed1993

[Experimental retinal branch vein occlusion. 4. Pathological changes in the middle and late stage].

Retinal branch vein occlusion in macaca monkeys (Macaca irus) was produced by dye laser photocoagulation, and observed histopathologically from five days to one year after photocoagulation. Ten days later, retinal edema and hemorrhage observed at an early stage gradually decreased. Two weeks later, capillary bed closure areas were observed in fluorescein angiography. The capillary closure was not reversible when disturbance of the retinal circulation continued for more than three or four days after photocoagulation. Three months later, dry retina was observed in the capillary bed closure areas. One year later, the retina was severely degenerated and thinned. In these retinal areas, capillary lumens observed microscopically were occluded by cellular components. Sheathing of large veins was observed in these retinal areas. The walls of these large veins were thick and fell into hyaline degeneration. Their lumens were narrowed or obstructed. During the period of observation, retinal neovascularization was not observed.

Animals↗
PubMed1998

Gene expression of insulin-like growth factor-I, its receptor and binding proteins in retina under hypoxic conditions.

Hypoxia is the main stimulus for neovascularization in the retina. Insulin-like growth factor-I (IGF-I) is thought to be one of the mediators of this process. Severe persistent hypoxia, as occurs in central retinal artery occlusion, is associated with less retinal neovascularization than relative hypoxia. To study the influence of different types of hypoxia on the IGF system, we used a model of neonatal rat retina that responds with neovascularization to a relative hypoxic stimulus produced by alternating oxygen concentrations in the respired air. We studied the influence of 24-hour hypoxia (10% oxygen), 48-hour hyperoxia (75% oxygen), and relative hypoxia (shifting from 48 hours in 75% oxygen to 24 hours in room air) on the gene expression of IGF-I, IGF-I receptor (IGF-IR), and IGF binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 in retina using a solution hybridization RNase protection assay. Hypoxia induced a significant increase in retinal IGF-IR (178%), IGFBP-2 (227%), and IGFBP-3 (317%) mRNA; however, retinal IGF-I mRNA was reduced, as well as serum growth hormone (GH). Relative hypoxia caused a similar but less pronounced trend in the gene expression of IGF-IR and the binding proteins, whereas retinal IGF-I mRNA was unchanged and serum GH was elevated. Both hypoxia and relative hypoxia may cause IGF system stimulation in the retina through upregulation of IGF-IR and IGFBPs. This stimulation may result in neovascularization. However, during hypoxia, low levels of tissue oxygenation and reduced local production of IGF-I may impede the neovascularization process.

Animals↗
PubMed2005

Enhanced anti-angiogenic effect of a deletion mutant of plasminogen kringle 5 on neovascularization.

Kringle 5 (K5), a proteolytic fragment of plasminogen, has been proved to be an angiogenic inhibitor. Previously, we have evaluated the effect of K5 on the vascular leakage and neovascularization in a rat model of oxygen-induced retinopathy. In this study, we expressed K5 and a deletion mutant of K5 (K5 mutant) in a prokaryocyte expression system and purified them by affinity chromatography. K5 mutant was generated by deleting 11 amino acids from K5 while retaining the three disulfide bonds. The anti-angiogenic activity of intact K5 and K5 mutant were compared in endothelial cells and retinal neovascularization rat model. K5 mutant inhibited the proliferation of primary human retinal capillary endothelial cells (HRCEC) in a concentration-dependent manner, with an apparent EC50 of approximate 35 nmol/L, which is twofold more potent than intact K5. In the even higher concentration range, K5 mutant did not inhibit pericytes from the same origin of HRCEC, which suggested an endothelial cell-specific inhibition. K5 mutant had no effect on normal liver cells and Bel7402 hepatoma cells even at high concentration range either. Intravitreal injection of the K5 and mutant in the oxygen-induced retinopathy rat model both resulted in significantly fewer neovascular tufts and nonperfusion area than controls with PBS injection, as shown by fluorescein angiography. Furthermore, K5 mutant exhibited more strong inhibition effect on neovascularization than intact K5 by quantification of vascular cells. These results suggest that this K5 deletion mutant is a more potent angiogenic inhibitor than intact K5 and may have therapeutic potential in the treatment of those disorders with neovascularization, such as solid tumor, diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, and hyperplasia of prostate.

Angiogenesis Inhibitors↗
PubMed1987

Phacoemulsification and implantation of posterior chamber intraocular lens in eyes with quiescent proliferative diabetic retinopathy.

A phacoemulsification procedure, combined with an "in-the-bag" lens implantation, was performed on ten eyes that once had proliferative diabetic retinopathy (PDR). The ten eyes were in eight patients who had a 20-plus year history of either type I or type II diabetes mellitus. All eyes had reached the "quiescent" state of diabetic retinopathy 2-13 years before the cataract surgery through either argon laser pan retinal photocoagulation and/or pars plana vitrectomy. Nine of ten eyes remained completely free of retinal neovascularization and rubeosis iridis, with follow-up periods between 1.5 and 5 years. One eye has been lost to recurrent vitreous hemorrhages and an inoperable retinal detachment.

Adult↗
PubMedDate not supplied

Neovascular glaucoma after branch retinal artery occlusion.

BACKGROUND: Neovascular glaucoma (NVG) occurring after branch retinal artery occlusion (BRAO) might not be as rare as previously thought. We report a case of unilateral NVG after BRAO. CASE: A 72-year-old man with chronic heart failure suffered from BRAO in the left eye. Funduscopic examination showed retinal edema and many cotton wool spots in the superotemporal retina. OBSERVATIONS: Five weeks later, he had increased blurring of vision due to a second BRAO in the inferotemporal retina of the left eye. Three days later, he felt pain and had severe visual loss in the left eye. In the presence of angle neovascularization, intraocular pressure (IOP) in the left eye rose to 35 mmHg. Immediate focal photocoagulation to the affected retina diminished the neovascularization and lowered the IOP. CONCLUSION: It is possible for NVG to occur as a complication of BRAO.

Aged↗
PubMed2005

Attenuation of retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy in Bcl-2-/- mice.

Bcl-2 is a death repressor that protects cells from apoptosis mediated by a variety of stimuli. Bcl-2 expression is regulated by both pro- and anti-angiogenic factors; thus, it may play a central role during angiogenesis. However, the role of bcl-2 in vascular development and growth of new vessels requires further delineation. In this study, we investigated the physiological role of bcl-2 in development of retinal vasculature and retinal neovascularization during oxygen-induced ischemic retinopathy (OIR). Mice deficient in bcl-2 exhibited a significant decrease in retinal vascular density compared to wild-type mice. This was attributed to a decreased number of endothelial cells and pericytes in retinas from bcl-2-/- mice. We observed, in bcl-2-/- mice, delayed development of retinal vasculature and remodeling, and a significant decrease in the number of major arteries, which branch off from near the optic nerve. Interestingly, hyaloid vessel regression, an apoptosis-dependent process, was not affected in the absence of bcl-2. The retinal vasculature of bcl-2-/- mice exhibited a similar sensitivity to hyperoxia-mediated vessel obliteration compared to wild-type mice during OIR. However, the degree of ischemia-induced retinal neovascularization was significantly reduced in bcl-2-/- mice. These results suggest that expression of bcl-2 is required for appropriate development of retinal vasculature as well as its neovascularization during OIR.

Aging↗
PubMedDate not supplied

Surgical management of retinal detachment secondary to acute retinal necrosis: clinical features, surgical techniques, and long-term results.

PURPOSE: To describe the clinical features of complicated retinal detachment secondary to acute retinal necrosis (ARN) and to present the long-term results of vitreous surgery in these cases. METHODS: A retrospective study was conducted on 16 immunocompetent patients (18 eyes). The average follow-up period was 60 months. RESULTS: Proliferative vitreoretinopathy (PVR) grade C, with the predominance of anterior PVR, and characteristic changes in the vitreous base area were present in all cases before surgery. All eyes underwent vitrectomy, membrane peeling, endolaser photocoagulation, and intraocular tamponade without scleral buckling. Additional procedures were performed in 13 eyes. Retinal reattachment was achieved in the 18 eyes (100%) in the short term. Variable degrees of reproliferation occurred in all cases after surgery. Other delayed complications included ocular hypotony, macular pucker, peripheral retinal neovascularization, and severe preretinal fibrosis. Improvement of visual acuity occurred in 13 eyes (72.2%). Eleven eyes (61.1%) achieved final ambulatory visual acuity of 5/200 or better. CONCLUSIONS: Rhegmatogenous retinal detachment secondary to ARN has characteristic clinical features. Severe proliferative vitreoretinopathy with the predominance of anterior PVR develops rapidly. Reproliferation is the most important late postvitrectomy complication necessitating multiple surgical procedures in these cases. The visual results remain unfavorable due to the destructive nature of ARN.

Adult↗
PubMed1998

Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531.

OBJECTIVE: The authors tested the antiangiogenic properties of an orally administered protein kinase-Cbeta inhibitor, LY333531, in a pig model of preretinal neovascularization caused by retinal branch vein occlusion to determine the effectiveness of this therapy in preventing intraocular neovascularization from an ischemic stimulus. METHODS: In 20 eyes of 10 pigs, branch retinal vein occlusions were created in a standardized manner using photodynamic thrombosis with rose bengal dye and thermal burns from an argon laser with green light. Five animals received 1 mg/kg LY333531 daily in two oral doses, and five animals were untreated. The eyes were followed clinically for 12 weeks with ophthalmoscopy, fundus photography, and fluorescein angiography. A standardized grading system permitted masked assessment of disc proliferations using stereo fundus photographs. After the pigs were killed, all neovascularization was confirmed histopathologically in a masked fashion and a final grade was assigned to each eye. The Mann-Whitney test was used for statistical analysis of the median values of the unpaired data between the two eyes of each animal (data were rounded up). RESULTS: Significant inhibition of neovascularization was observed in eyes from animals treated with the study drug (P = 0.03). Although some of the treated eyes demonstrated no clinically evident new vessels, histopathologic and photographic analysis demonstrated fine new vessels on the optic disc in all eyes (mean grade 1.9). All the untreated eyes developed clinically evident neovascularization (mean grade 3.1). The oral drug was well tolerated, and no side effects were documented. CONCLUSIONS: A specific protein kinase-Cbeta inhibitor, LY333531, effectively inhibited preretinal and optic nerve head neovascularization in the pig model of branch retinal vein occlusion. This was consistent with the known pathways of signal transduction by growth factors in activated cells and suggested that inhibition of this key regulatory isozyme is effective in the treatment of ischemia-mediated neovascular diseases.

Administration, Oral↗
PubMed2003

Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model.

Overexpression of vascular endothelial growth factor (VEGF) is implicated in the development of vascular leakage and retinal neovascularization in diabetic subjects. The objective of this study was to determine whether celecoxib, a selective cyclooxygenase-2 enzyme inhibitor, reaches ocular tissues following oral administration and inhibits the retinal VEGF expression and vascular leakage in a streptozotocin-induced diabetic rat model. After administering a single intraperitoneal injection of streptozotocin (60 mg/kg) to Sprague-Dawley rats and ensuring the induction of diabetes at the end of 24 h, celecoxib was administered b.i.d. by oral gavage (50 mg/kg). On day 8, the animals were sacrificed and the retinal VEGF and cyclooxygenase-2 mRNA levels, ocular tissue celecoxib concentrations, and the vitreous/plasma protein ratio were determined. In diabetic rats, the retinal VEGF mRNA expression was 2.3-fold compared to controls, with a corresponding increase in cyclooxygenase-2 mRNA expression. Celecoxib treatment inhibited VEGF mRNA expression without any significant reduction in cyclooxygenase-2 mRNA. Furthermore, the retinal vascular leakage estimated as vitreous to plasma protein ratio increased in diabetic animals from 0.35+/-0.1 to 1.1+/-0.1 and celecoxib treatment significantly decreased this ratio to 0.4+/-0.1. Celecoxib levels were 24.8+/-6.6, 1.9+/-1, 1.7+/-0.8, and 6.9+/-0.9 ng/mg in the retina, vitreous, lens, and cornea, respectively. The plasma celecoxib levels were 85+/-24 ng/ml. Thus, celecoxib reaches the retina after oral administration and reduces diabetes-induced retinal VEGF mRNA expression and vascular leakage by inhibiting the activity of cyclooxygenase-2 enzyme.

Animals↗
PubMed2001

Effects of insulin-like growth factor-1 on retinal endothelial cell glucose transport and proliferation.

Insulin-like growth factor-1 (IGF-1) plays important roles in the developing and mature retina and in pathological states characterized by retinal neovascularization, such as diabetic retinopathy. The effects of IGF-1 on glucose transport and proliferation and the signal transduction pathways underlying these effects were studied in a primary bovine retinal endothelial cell (BREC) culture model. IGF-1 stimulated uptake of the glucose analog 2-deoxyglucose in a dose-dependent manner, with a maximal uptake at 25 ng/mL (3.3 nM) after 24 h. Increased transport occurred in the absence of an increase in total cellular GLUT1 transcript or protein. IGF-1 stimulated activity of both protein kinase C (PKC) and phosphatidylinositol-3 kinase (PI3 kinase), and both pathways were required for IGF-1-mediated BREC glucose transport and thymidine incorporation. Use of a selective inhibitor of the beta isoform of PKC, LY379196, revealed that IGF-1 stimulation of glucose transport was mediated by PKC-beta; however, inhibition of PKC-beta had no effect on BREC proliferation. Taken together, these data suggest that the actions of IGF-1 in retinal endothelial cells couple proliferation with delivery of glucose, an essential metabolic substrate. The present studies extend our general understanding of the effects of IGF-1 on vital cellular activities within the retina in normal physiology and in pathological states such as diabetic retinopathy.

3-O-Methylglucose↗
PubMed1994

Oxygen-induced retinopathy in the rat: relationship of retinal nonperfusion to subsequent neovascularization.

PURPOSE: To confirm a relationship between oxygen-induced retinal vasoattenuation and subsequent abnormal neovascularization in the newborn rat. METHODS: Beginning at birth, some litters of Sprague-Dawley rats were exposed to 80% constant oxygen while others received oxygen varying between 40% and 80% in a cyclic fashion. The frequency of the change in inspired oxygen (FiO2) was either 6, 12, 24, or 48 hours. The exposures periods lasted for 14 days, at which time some rats from each exposure group were sacrificed and assessed for retinal vasoattenuation with injection of fluorescein-labeled dextran. The remaining rats from each group were transferred at day 14 from the hyperoxic atmosphere to room air for an additional 4 days. These animals were then killed and assessed for retinal neovascularization by staining for vascular ADPase activity. RESULTS: Of all rats raised in variable oxygen, 62% exhibited abnormal retinal neovascularization after 4 days in room air. Only 18% of the rats exposed to constant oxygen responded with abnormal neovascularization. Among the four groups of variable oxygen-exposed rats, there was a direct correlation (R2 = 0.96) between degree of retinal avascularity upon removal from oxygen and the propensity for subsequent abnormal neovascularization. Constant oxygen-exposed rats did not exhibit this relationship. This exposure produced the greatest retinal avascularity upon removal from oxygen but the lowest incidence of abnormal neovascularization after 4 days in room air. CONCLUSIONS: Retinal avascularity may not be the single overriding stimulus for neovascularization in oxygen-induced retinopathy. Other hypotheses bear consideration, including the possibility that variable oxygen leads directly to vascular endothelial cell mitosis, a common retinal manifestation of ischemia-reperfusion.

Animals↗
PubMedDate not supplied

Late complications in branch retinal vein occlusion.

Neovascularization in branch retinal vein occlusion usually develops 6-12 months after the onset of the disease, although some cases have been reported in which neovascularization and subsequent vitreous haemorrhage developed 2-3 years later. This is a report of nine cases of late appearance of vitreous haemorrhage due to branch retinal vein occlusion, which occurred 3-6 years after the initial onset of the disease. In two of these nine cases the vitreous haemorrhage was very profound and had to be managed by vitrectomy. We have studied the remaining seven cases, which had retinal ischaemia and optic disc or retinal neovascularization documented by fluorescein angiographic examination. Laser coagulation was applied in these seven cases, which resulted in considerable regression of the neovascularization and absorption of the vitreous haemorrhage. In one out of the seven cases recurrent vitreous haemorrhages appeared and it was finally treated by vitrectomy. Visual acuity improved in six of the seven cases. The follow-up period ranged from 12 to 48 months. The late appearance of the ischaemic type of branch retinal vein occlusion with neovascularization can be attributed to the change in character of the initially mild oedematous form of the disease. Partial posterior vitreous detachment and traction exerted at some later stage upon the neovascularization could be additional factors of the late appearance of vitreous haemorrhage. Patients with branch retinal vein occlusion should be followed up regularly over a long period of time in order to avoid late complications of the disease, such as vitreous haemorrhage following optic disc or retinal neovascularization.

Aged↗
PubMed1995

Increased thromboxane-mediated contractions of retinal vessels of newborn pigs to peroxides.

The vasomotor effects of three peroxides (H2O2, cumene hydroperoxide, and t-butyl hydroperoxide) on the retinal vasculature, as well as the role of thromboxane in these effects, were studied using time-frame photography of isolated eyecup preparations from newborn and adult pigs. All three peroxides caused constriction of retinal arteries and veins, and these effects were greater in the newborn than in the adult. The cyclooxygenase inhibitor indomethacin, the thromboxane synthase blocker CGS-13080, and the thromboxane receptor blockers GR-32191B and L-670,596 inhibited the peroxide-induced vasoconstriction. The peroxides also increased thromboxane levels in the retina, and this increase was greater in newborn than in adult tissues. Both indomethacin and CGS-13080 prevented the peroxide-induced increase in retinal thromboxane. The thromboxane analogue U-46619 also produced constriction of newborn and adult retinal vessels, but its effects on the retinal veins of newborn pigs were less than those on adult veins. Data indicate an important role for increased production of thromboxane in the relative increase in the vasoconstrictor effects of peroxides on the newborn retinal vasculature. These findings suggest that the vasoconstriction and occlusion after oxidative stresses, which precede retinal neovascularization, are mediated by thromboxane.

Aging↗
PubMed2006

Recombinant non-collagenous domain of alpha2(IV) collagen causes involution of choroidal neovascularization by inducing apoptosis.

Vascular endothelial cells receive proangiogenic or antiangiogenic signals from components of extracellular matrix (ECM) depending upon the situation and many molecular signals can have opposite effects in different vascular beds. Tissue inhibitor of metalloproteinase 1 is antiangiogenic in several tissues, but promotes retinal neovascularization. When cleaved from native collagens, several of the non-collagenous domains (NC1) of basement membrane collagens have antiangiogenic effects in some tissues, but this is context dependent for the NC1 of the alpha 1 chain of collagen IV. It is critical to examine effects in several well-defined model systems before assuming that an ECM component is universally antiangiogenic. In this study, we examined the effects of a recombinant fragment of NC1 of the alpha 2 chain of type IV collagen (alpha2(IV)NC1) in a well-characterized model of ocular neovascularization. Intravitreous or periocular injections of alpha2(IV)NC1 caused selective apoptosis of endothelial cells participating in neovascularization resulting in suppression of neovascularization when the peptide was given prior to onset of new vessel sprouting. Importantly, when the peptide was given after neovascularization had already developed, it caused the new vessels to regress. This suggests that alpha2(IV)NC1, which has previously been shown to suppress tumor angiogenesis in xenograft models, is also a strong antiangiogenic agent in the choroid and is a therapeutic candidate for treatment of neovascular age-related macular degeneration.

Angiogenesis Inhibitors↗
PubMed1988

Surgical decompression of branch retinal vein occlusions.

Many patients with branch retinal vein occlusions can develop significant long-term diminution of vision due to such complications as macular edema, retinal neovascularization, and vitreous hemorrhage. One of us (S.C.) developed a new surgical procedure that involves sectioning or decompression of the common sheath connecting the artery and vein at the crossing where a branch retinal vein occlusion occurs. The patient whose case we report had a visual acuity improvement from 20/200-2 to 20/25+1 eight months after surgery.

Female↗