Retinal pigment epithelial tear weeks following photodynamic therapy with verteporfin for choroidal neovascularization secondary to pathologic myopia.
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Adult↗
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Results for “Neovascularization, Pathologic”
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[Correlation of pathological features of surgically excised choroidal neovascular membranes with age-related macular degeneration and indocyanine green videoangiographic findings].
We surgically excised subfoveal neovascular membranes from eight patients with age-related macular degeneration. The correlation of the histopathological features of choroidal neovascularization and preoperative indocyanine green (ICG) videoangiographic findings were studied. Neovascular membranes which demonstrated hyperfluorescence at an early phase of ICG videoangiography had many vascular channels and a large lumen without enclosure of retinal pigment epithelium (RPE). Fibrovascular tissues contained small vessels with fibrotic stroma that showed hyperfluorescence only at a late phase of ICG videoangiography. In contrast, the membrane which showed hypofluorescence of ICG videoangiography was composed of paucivascular fibrotic tissue covered extensively with RPE. Moreover, newly formed vessels with proliferative endothelium could be observed in the neovascular membranes that showed weak fluorescence or hypofluorescence. These results could provide a morphological basis for the interpretation of ICG videoangiographic features of choroidal neovascularization. It also may be useful in planning the treatment for subfoveal neovascular membranes.
Aged↗
VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization.
Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte-mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.
Animals↗
Aminopeptidase a is a constituent of activated pericytes in angiogenesis.
Monoclonal antibody (MAb) RC38 recognizes a human renal antigen of 160 kD recently identified as human aminopeptidase A (APA; EC 3.4.11.7). This ectoenzyme is able to hydrolyse selectively N-terminal glutamyl and aspartyl residues from oligopeptides. By enzyme histochemistry, APA activity has also been localized in the microvessels of all organs in animals and man. The purpose of this study was to investigate the distribution of human APA as recognized by MAb RC38 in the microvasculature of normal human tissues and pathological conditions associated with neovascularization. Unexpectedly, in normal tissues vascular staining with MAb RC38 was generally weak and often absent, while in tumours, granulation tissue, and chronic synovitis, marked microvascular staining was demonstrated. By immuno-electron microscopy, the antigen was found on the cell membrane of activated pericytes and their processes in the tumour vasculature. RC38 expression could not be detected on cultured human endothelial cells or pericytes. These observations suggest that pericyte expression of a subtype of APA (as recognized by MAb RC38) is markedly enhanced in the vasculature of tumours and wound healing tissue as compared with normal resting tissues. This provides further evidence of the altered state of pericytes in these conditions. Pericyte APA may be involved in the metabolism of biologically active oligopeptides during neovascularization, supporting a regulatory role of pericytes in this process. In addition, MAb RC38 may be useful as a marker of pericyte activation in tissue sections.
Aminopeptidases↗
Manipulating angiogenesis. From basic science to the bedside.
Considerable progress has been made recently in understanding the molecular mechanisms of angiogenesis, which like most other biological processes is the result of subtle and often complex interactions between molecules that have regulatory (eg, cytokines and their receptors) and effector (eg, extracellular matrix, integrins, and proteases) functions. The title of this review was chosen to reflect a recent trend in which knowledge acquired through a molecular/cell biological approach is being rapidly transferred to the clinical setting. As a result, by manipulating angiogenesis either positively or negatively, considerable therapeutic benefit can now be envisaged in physiological and pathological settings in which neovascularization is a prominent component.
Animals↗
Treatment frequency and visual outcome in subfoveal choroidal neovascularization related to pathologic myopia treated with photodynamic therapy.
BACKGROUND: The purpose of this study was to examine the influence of treatment frequency on visual acuity of patients with PDT treatment for subfoveal predominantly classic CNV related to pathological myopia. DESIGN: Retrospective case series. METHODS: Thirty-seven patients with subfoveal predominantly classic CNV caused by pathologic myopia and treated with PDT were included. All patients received a full ophthalmic examination, including best-corrected visual acuity, slit-lamp biomicroscopy, fundus photography and fluorescein angiography, before first treatment and every 3 months thereafter. Photodynamic therapy was performed according to standard protocol. Main outcome measurements were visual acuity and treatment frequency. RESULTS: The number of treatments received was 3.35+/-1.83 (average: 1-7). In 12 eyes (32.43%); the BCVA was stable or increased during the entire follow-up period. In eight eyes (21.62%), the BCVA decreased and did not return to the baseline values. A transient loss of visual acuity (over 3-9 months) with subsequent improvement in visual function was found in 68% (17 eyes). A gain of three or more lines compared with lowest BCVA was found in 56% (14 eyes). The number of treatments did not correlate with baseline BCVA, greatest linear dimension of CNV at baseline or with the change of BCVA from baseline. In cases with transient worsening of BCVA, the recovery of visual acuity correlated significantly with the number of treatments (r=-0.522, P<0.05; Spearman rank correlation) received. CONCLUSION: Visual acuity recovery correlates with the number of PDT re-treatments; in many cases, an improvement in visual function after temporary decrease of BCVA can be observed after re-treatment according to current treatment guidelines. The number of PDT treatments has no negative effect on the visual outcome in subfoveal CNVs caused by pathological myopia.
Adult↗
Pathology of anterior chamber angle in diabetic neovascular glaucoma: extension of corneal endothelium onto iris surface.
The purpose of this study is to elucidate the extension of the corneal endothelium onto the iris surface, a condition which has been found in the eyes with rubeosis iridis in various ocular disorders. Histopathology of the anterior chamber angle was studied by electron microscopy in 6 eyes with neovascular glaucoma occurring in the advanced stage of diabetic retinopathy. Histopathological findings embraced extensive peripheral anterior synechiae occluding the filtration angle and fibrovascular tissue on the anterior surface of the iris. In addition, formation of a continuous layer of endothelium was observable on the surface of the iris facing the anterior chamber in the 6 eyes. The newly formed endothelium was continuous with the corneal endothelium at the pseudo-angle formed by the attachment of peripheral anterior synechiae. Two types of corneal endothelial cells were found near the pseudoangle, one type with degenerative changes and the other apparently engaged in normal metabolic activity. It may be assumed from these findings that, while the corneal endothelium undergoes degeneration, new cells of unknown origin proliferate on the posterior corneal surface to replace the disrupted corneal endothelium and extend onto the iris surface.
Adult↗
Thiolutin, an inhibitor of HUVEC adhesion to vitronectin, reduces paxillin in HUVECs and suppresses tumor cell-induced angiogenesis.
Recent studies have shown that integrin alpha v beta 3, a receptor for vitronectin, plays an important role in tumor-induced angiogenesis and tumor growth and that antagonists of alpha v beta 3 inhibit angiogenic processes including endothelial cell adhesion and migration. On the other hand, most inhibitors of integrin alpha v beta 3 are peptide antagonists that include the Arg-Gly-Asp (RGD) motif. We therefore reasoned that non-peptide inhibitors of endothelial cell adhesion to vitronectin might be useful for inhibition of tumor angiogenesis in vivo. We screened for low-molecular-weight natural products able to inhibit adhesion of human umbilical vein endothelial cells (HUVECs) to vitronectin, and pyrrothine group compounds including aureothricin, thioaurin and thiolutin were isolated from microbial culture broths. Of these compounds, thiolutin inhibited adhesion of HUVECs to vitronectin the most effectively (IC(50), 0.83 microM). In vivo experiments showed that thiolutin significantly suppressed angiogenesis induced by tumor cells (S-180), a pathological form of neovascularization, in a mouse dorsal air sac assay system. To explore the mechanism of inhibition of HUVEC adhesion to vitronectin by thiolutin, we examined the effect of this agent on intracellular cell adhesion signaling. We found that the amount of paxillin in HUVECs was significantly reduced by thiolutin treatment, while those of other focal adhesion proteins including vinculin and focal adhesion kinase (FAK) were not. Metabolic labeling experiments showed that thiolutin enhanced degradation of paxillin in HUVECs. Protease inhibitors (MG115 and E64-D) decreased the rate of degradation of the paxillin induced by thiolutin and partially restored thiolutin-induced inhibition of HUVEC adhesion to vitronectin. Based on these findings, we concluded that thiolutin, an inhibitor of HUVEC adhesion to vitronectin, reduces the paxillin level in HUVECs and suppresses tumor cell-induced angiogenesis in vivo.
Animals↗
The pathology of abortive neovascular outgrowths from the retina.
Seven abortive neovascular outgrowths (ANVOs) from diabetic retinas were obtained for examination either by biopsy during pars plana vitrectomy (2) or after discovery within enucleated globes (5). Scanning and electron microscopical, histochemical, immunohistochemical and retinal digest techniques were used. The ANVOs consisted of nodules of vessels without an extravascular fibrous component. Two of them contained aneurysm-like dilatations of constituent vessels, and all the specimens showed gross hyaline thickening of the vessel walls. The vascular sclerosis was probably due to accumulation of plasma proteins in the walls of the damaged vessels, which contributes to their involution seen clinically after retinal photocoagulation.
Adult↗
Radiotherapy for subfoveal neovascularization associated with pathological myopia: a pilot study(1)
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Journal Article↗
Gene therapy for proliferative ocular diseases.
Proliferative ocular diseases encompass a wide variety of pathological processes with adverse cellular differentiation, proliferation and migration as common features. Pathologies may involve neovascular responses associated with diabetic retinopathy, retinopathy of prematurity or age-related macular degeneration. These diseases are quite prevalent and account for substantial visual impairment and blindness worldwide. Although treatment strategies are largely surgical, advances in our understanding of the proteins crucial to cell transdifferentiation, proliferation and migration, along with better gene transfer techniques, have greatly increased the potential for biological treatment options. In this report, the most common proliferative ocular vascular diseases and existing therapeutic modalities will be reviewed and an overview of possible gene therapy options will be discussed, along with potential candidate genes.
Adenoviridae↗
Inhibition of angiogenesis by growth factor receptor bound protein 2-Src homology 2 domain bound antagonists.
Growth factor receptor bound protein 2 (Grb2) is an intracellular adaptor protein that participates in the signal transduction cascades of several angiogenic factors, including hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor. We described previously the potent blockade of hepatocyte growth factor-stimulated cell motility, matrix invasion, and epithelial tubulogenesis by synthetic Grb2-Src homology 2 (SH2) domain binding antagonists. Here, we show that these binding antagonists block basic morphogenetic events required for angiogenesis, including hepatocyte growth factor-, vascular endothelial growth factor-, and basic fibroblast growth factor-stimulated endothelial cell proliferation and migration, as well as phorbol 12-myristate 13-acetate-stimulated endothelial cell migration and matrix invasion. The Grb2-SH2 domain binding antagonists also impair angiogenesis in vitro, as shown by the inhibition of cord formation by macrovascular endothelial cells on Matrigel. We further show that a representative compound inhibits angiogenesis in vivo as measured using a chick chorioallantoic membrane assay. These results suggest that Grb2 is an important mediator of key proangiogenic events, with potential application to pathologic conditions where neovascularization contributes to disease progression. In particular, the well-characterized role of Grb2 in signaling cell cycle progression together with our present findings suggests that Grb2-SH2 domain binding antagonists have the potential to act as anticancer drugs that target both tumor and vascular cell compartments.
Adaptor Proteins, Signal Transducing↗
Leukocyte antigen CD34 is expressed by a subset of cultured endothelial cells and on endothelial abluminal microprocesses in the tumor stroma.
It has been reported that the human haemopoietic progenitor cell antigen CD34 is also expressed by vascular structures. To investigate its precise vascular localization, we have studied the cellular and subcellular distribution of CD34 in normal tissues and pathologic tissues with neovascularization. In normal resting tissues, anti-CD34 antibodies, ICH3 and QBEND-10 predominantly stain the luminal endothelial membrane, whereas the abluminal membrane is negative or weakly positive. In contrast, a striking staining of endothelial abluminal microprocesses (EAM) was found in the tumor stroma. These structures, measuring up to 20 microns in length, could be observed in thick vibratome sections both at the tips of vascular sprouts and, also frequently, on fully formed microvessels. The number of vascular sprouts and EAM varied widely between different tumors. CD34-stained EAM were sparsely present in fetal tissue of 10 weeks gestation, but they could not be demonstrated in granulation tissue of wound healing. By immunoelectron microscopy, the EAM were continuous with the cytoplasm of endothelial cells showing an immature phenotype as seen in regeneration. In cultured human umbilical vein endothelium, CD34 was preferentially found on a small subset of cells with the morphologic appearance of migrating cells. These findings suggest that CD34 is an endothelial marker for EAM present during angiogenesis.
Antibodies, Monoclonal↗
PEDF derived from glial Müller cells: a possible regulator of retinal angiogenesis.
A precise balance between stimulators and inhibitors of angiogenesis, such as vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), respectively, is essential for angiogenic homeostasis in ocular tissues. Retinal hypoxia is accompanied by some pathological conditions that may promote intraocular neovascularization. Here we demonstrate that retinal glial (Müller) cells express and release pigment epithelium-derived factor (PEDF). Decreasing oxygen concentrations cause strong attenuation of PEDF release resulting in enhanced VEGF/PEDF ratios. Exposure of Müller cells to VEGF suppressed PEDF release in a dose-dependent manner. This may represent a novel mechanism of ocular angiogenic homeostasis sufficient in the control of PEDF levels during normoxia or mild hypoxia but supplemented by other (hitherto unknown) mechanisms in cases of strong hypoxia. In spite of the enhanced VEGF/PEDF ratios resulting from hypoxia, conditioned media of Müller cells failed to stimulate additional proliferation of retinal endothelial cells. These findings suggest that in the ischemic retina, Müller cells generate a permissive condition for angiogenesis by secreting more VEGF and less PEDF, but the onset of retinal endothelial cell proliferation requires another triggering signal that remains to be identified.
Animals↗
The biology of VEGF and its receptors.
Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.
Animals↗
Renal cell carcinoma and tumor thrombus neovascularity: MR demonstration with pathologic correlation.
A case of renal granular cell carcinoma with inferior vena cava and right atrium involvement is presented. Spin-echo and single breath-hold gradient-recalled-echo magnetic resonance pulse sequences demonstrate a patchy flow signal within the cavoatrial thrombus. This pattern, in correlation with the histopathologic findings, represents tumoral neovascularity characteristic of renal carcinoma venous invasion, which was previously reported by angiography, computed tomography, and color Doppler duplex ultrasound.
Aged↗
Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.
PURPOSE: To report the biologic effect of intravitreal bevacizumab in patients with retinal and iris neovascularization secondary to diabetes mellitus. DESIGN: Interventional, consecutive, retrospective, case series. PARTICIPANTS: Forty-five eyes of 32 patients with retinal and/or iris neovascularization secondary to diabetes mellitus. METHODS: Patients received intravitreal bevacizumab (6.2 microg-1.25 mg). Ophthalmic evaluations included nonstandardized Snellen visual acuity (VA), complete ophthalmic examination, fluorescein angiography, and optical coherence tomography. MAIN OUTCOME MEASURES: Change in fluorescein angiographic leakage of the proliferative diabetic retinopathy (PDR). Secondary outcomes included changes in Snellen VA. RESULTS: No significant ocular or systemic adverse events were observed. All patients with neovascularization demonstrated by fluorescein angiography (44/44 eyes) had complete (or at least partial) reduction in leakage of the neovascularization within 1 week after the injection. Complete resolution of angiographic leakage of neovascularization of the disc was noted in 19 of 26 (73%) eyes, and leakage of iris neovascularization completely resolved in 9 of 11 (82%) eyes. The leakage was noted to diminish as early as 24 hours after injection. In addition to the reduction in angiographic leakage, the neovascularization clinically appeared to involute in many patients with a reduction in the caliber or presence of perfused blood vessels. In 2 cases, a subtle decrease in leakage of retinal or iris neovascularization in the fellow uninjected eye was noted, raising the possibility that therapeutic systemic levels were achieved after intravitreal injection. Recurrence of fluorescein leakage varied. Recurrent leakage was seen as early as 2 weeks in one case, whereas in other cases, no recurrent leakage was noted at last follow-up of 11 weeks. CONCLUSIONS: Short-term results suggest that intravitreal bevacizumab is well tolerated and associated with a rapid regression of retinal and iris neovascularization secondary to PDR. A consistent biologic effect was noted, even with the lowest dose (6.2 microg) tested, supporting proof of concept. The observation of a possible therapeutic effect in the fellow eye raises concern that systemic side effects are possible in patients undergoing treatment with intravitreal bevacizumab (1.25 mg), and lower doses may achieve a therapeutic result with less risk of systemic side effects. Further study is indicated.
Adult↗
Antiangiogenic effects of somatostatin analogues.
Inhibition of angiogenesis has become a target for antineoplastic therapy and for treatment of retinal neovascularization. The presence of somatostatin receptors on tumour cells and on the proliferating vascular endothelium has led to several in vitro and in vivo studies to investigate the antiproliferative and antiangiogenic effects of somatostatin analogues. Currently available data suggest that somatostatin analogues might inhibit angiogenesis directly through somatostatin receptors present on endothelial cells and also indirectly through the inhibition of growth factor secretion such as IGF-I and vascular endothelial growth factor (VEGF) and reducing monocyte chemotaxis. However, beneficial effects on inhibition of neovascularization have been questioned by some studies. More work is therefore required to firmly establish the role of somatostatin analogues as potential antiangiogenic therapy. The currently available somatostatin analogues have high affinity for somatostatin receptor subtype 2 (sst2) and, to a lesser extent, sst5 and sst3. However, because vascular endothelial cells express several types of somatostatin receptors, it will be important to investigate somatostatin analogues with different receptor subtype affinities, which might increase the spectrum of available therapy for tumours.
Angiogenesis Inhibitors↗