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PubMed1992

Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer.

Animal models suggest a role for new vessel formation (angiogenesis) in tumours with metastatic potential, and there is some evidence that this is true for human tumours. What is needed is a sensitive and specific label for endothelial cells, and one candidate would be a monoclonal antibody to platelet/endothelial cell adhesion molecule (PECAM). We have counted microvessels in 103 primary breast cancers using the JC70 antibody to PECAM (or CD31). We compared our findings with various pathological indicators (lymph node status and tumour grade, size, and type and markers (oestrogen receptor, and c-erbB-2 expression and detection of mutant p53). Tumours showed significantly higher vascularisation than normal breast tissue and the number of blood vessels/mm2 was significantly associated with node metastasis. Only 2 out of 50 tumours with 99 vessel/mm2 or less were node positive whereas 31 out of 39 tumours with counts above 140/mm2 were positive (p < 0.0001). Tumour size and grade also correlated with node metastasis and vascularisation also increased with the size of the primary and with poor differentiation. However, within each subgroup of size or differentiation tumours without node involvement had much lower vascular counts, and multivariate analysis showed that vascular count alone explains the association of size and grade with node metastasis. Other markers, conventional or novel, did not correlate with vascularisation. Even with the short follow-up in this series, vascular counts correlated with early death. These results suggest that angiogenesis is closely linked to metastasis, that it is acquired at a critical density of vessels, and that this process occurs as tumours enlarge or become more poorly differentiated. Counting of newly formed microvessels stained with endothelium-specific antibodies may prove to be a useful tool in the early detection of metastatic potential and in the selection of patients for whom anti-angiogenesis drugs might be beneficial.

Antigens, Differentiation, Myelomonocytic↗
PubMed1990

Chemotaxis of human microvessel endothelial cells in response to acidic fibroblast growth factor.

Migration of microvessel endothelial cells (MEC) in response to angiogenic stimuli is a key aspect of angiogenesis, whether in physiologic or pathologic situations. In this work, we provide a rigorous quantitative assessment of the chemokinetic and chemotactic responses of human MEC to acidic fibroblast growth factor (aFGF). A uniform concentration of 1 micrograms/ml of heparin was included in most experiments to exploit heparin's potentiating effect on aFGF activity. The migration is measured in an under-agarose assay with a linear geometry, and evaluated in terms of the random motility and chemotaxis coefficients, mu and chi, which are defined in a mathematical model. The change in value of mu with changes in aFGF concentration provides a quantitative description of the stimulated random motility response, a process known as chemokinesis. This allows the true directional response in gradients to be quantified by the chemotaxis coefficient, chi, and its variation with attractant concentration. The effect of aFGF on MEC random motility is relatively small, with the random motility coefficient ranging from 4.6 +/- 0.4 x 10(-9) to 9.9 +/- 0.3 x 10(-9) cm2/second (mean +/- SE) over four orders of magnitude of aFGF concentration (10(-11) to 10(-8) M). On the other hand, the magnitude of the chemotaxis coefficient at optimal concentrations is quite large (2600 +/- 750 cm2/second-M around 10(-10) M aFGF), demonstrating a significant degree of MEC directional sensitivity to aFGF gradients. The chemotaxis coefficient shows a biphasic dependence on aFGF concentration, suggestive of a receptor-mediated response in which apparent differences in receptor occupancy govern directional bias. These results provide support for the hypothesis that MEC chemotaxis accounts for the directed microvessel growth observed in angiogenesis.

Cell Movement↗
PubMed1992

The vascular endothelial growth factor proteins: identification of biologically relevant regions by neutralizing monoclonal antibodies.

Angiogenesis plays critical roles in organ development during embryonic and fetal life, wound healing and in a variety of pathological conditions. Vascular endothelial growth factor (VEGF) is a secreted growth factor specific for vascular endothelial cells which induces angiogenesis in vivo. To gain a better understanding of the physiological role of VEGF, we have generated and characterized four murine monoclonal antibodies (mAbs) using the 165 amino acid species of recombinant human VEGF as immunogen. These mAbs (A3.13.1, A4.6.1, B4.3.1 and B2.6.2) belong to IgG1 isotype and have high affinities for VEGF (dissociation constants range from 2.2 x 10(-9) to 4 x 10(-10) M). Two different epitopes were detected with these mAbs. One epitope is recognized by mAbs A3.13.1 and B2.6.2, and the other recognized by mAbs A4.6.1 and B4.3.1. The epitope recognized by mAb A4.6.1 appears to be continuous while mAb B2.6.2 recognizes a discontinuous epitope. MAb A4.6.1 recognized three species of VEGF generated by alternative splicing, VEGF121, VEGF165 and VEGF189 while mAb B2.6.2 binds only VEGF165 and VEGF189. Results using an in vitro bovine adrenal cortex endothelial cell proliferation assay, in in vivo vascular permeability assay and an in vivo embryonic chicken angiogenesis assay showed that mAb A4.6.1 has potent VEGF neutralizing activities. MAb A4.6.1 was shown to block the binding of VEGF to its receptor(s) suggesting the inhibitory mechanism for VEGF activities. These well-defined mAbs should be very powerful tools to understand the structure-function relationship of various domains of VEGF and may have therapeutic potential.

Adrenal Cortex↗
PubMed1991

Analysis of the roles of microvessel endothelial cell random motility and chemotaxis in angiogenesis.

The growth of new capillary blood vessels, or angiogenesis, is a prominent component of numerous physiological and pathological conditions. An understanding of the co-ordination of underlying cellular behaviors would be helpful for therapeutic manipulation of the process. A probabilistic mathematical model of angiogenesis is developed based upon specific microvessel endothelial cell (MEC) functions involved in vessel growth. The model focuses on the roles of MEC random motility and chemotaxis, to test the hypothesis that these MEC behaviors are of critical importance in determining capillary growth rate and network structure. Model predictions are computer simulations of microvessel networks, from which questions of interest are examined both qualitatively and quantitatively. Results indicate that a moderate MEC chemotactic response toward an angiogenic stimulus, similar to that measured in vitro in response to acidic fibroblast growth factor, is necessary to provide directed vascular network growth. Persistent random motility alone, with initial budding biased toward the stimulus, does not adequately provide directed network growth. A significant degree of randomness in cell migration direction, however, is required for vessel anastomosis and capillary loop formation, as simulations with an overly strong chemotactic response produce network structures largely absent of these features. The predicted vessel extension rate and network structure in the simulations are quantitatively consistent with experimental observations of angiogenesis in vivo. This suggests that the rate of vessel outgrowth is primarily determined by MEC migration rate, and consequently that quantitative in vitro migration assays might be useful tools for the prescreening of possible angiogenesis activators and inhibitors. Finally, reduction of MEC speed results in substantial inhibition of simulated angiogenesis. Together, these results predict that both random motility and chemotaxis are MEC functions critically involved in determining the rate and morphology of new microvessel network growth.

Cell Division↗
PubMed2025

The Involvement of PI3K-Akt Signaling in the Clinical and Pathological Findings of Idiopathic Multicentric Castleman Disease-Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, and Organomegaly and Not Otherwise Specified Subtypes.

Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder that is clinically classified into idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); and not otherwise specified (NOS). Although each subtype shows varying degrees of hypervascularity, no statistical data on the degree of vascularization have been reported. Additionally, the mechanisms underlying vascularization in each clinical subtype are poorly understood. Here, we aimed to clarify these mechanisms by evaluating the histopathological characteristics of each clinical subtype across 37 patients and performing a whole-transcriptome analysis focusing on angiogenesis-related gene expression. Histologically, TAFRO and NOS exhibited a significantly higher degree of vascularization than IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .002). In addition, the germinal centers (GCs) were significantly more atrophic in TAFRO than in IPL. In TAFRO and NOS, "whirlpool vessels" in GCs were seen in most cases (TAFRO, 9/9, 100%; NOS, 6/8, 75%) but not in IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .007). Likewise, immunostaining for Ets-related gene revealed higher levels in endothelial cells of GCs in TAFRO than in IPL (P = .014), and TAFRO and NOS were associated with a significantly higher number of endothelial cells in interfollicular areas compared with that in IPL (TAFRO vs IPL, P < .001; NOS vs IPL, P = .002). Gene expression analysis revealed that the PI3K-Akt signaling pathway was significantly enriched in the TAFRO and NOS (TAFRO/NOS) groups. This pathway, which may be activated by vascular endothelial growth factor A and some integrins, is known to affect angiogenesis by increasing vascular permeability, which may explain the clinical manifestations of anasarca and/or fluid retention in TAFRO/NOS. These results suggest that the PI3K-Akt pathway plays an important role in the pathogenesis of TAFRO/NOS.

Humans↗
PubMed1979

A modified filtering operation for neovascular glaucoma.

Thirteen patients with useful vision but suffering from uncontrollable neovascular glaucoma due to total angle closure were treated with modified filtering operations. Ten (77%) of the cases were controlled more than one year postoperatively. Most patients whose pressures were controlled maintained their preoperative visual acuities. These visual results appear to be better than those reported with cyclocryotherapy, where vision is usually lost despite satisfactory pressure control.

Adolescent↗
PubMed1979

Iris neovascular tufts. Relationship to rubeosis, insulin, and hypotony.

Iris neovascular tufts are abnormal proliferations of twisted microcapillary loops that project from the iris pupillary border. They appear to be a morphologic variant of rubeosis iridis. This study searched for iris neovascular tufts by biomicroscopy and iris fluorescein angiography. They were found in two of 16 (12.5%) myotonic dystrophy patients, in two of 30 (6.7%) maturity-onset diabetics, and in zero of 14 (0%) juvenile-onset diabetics. Myotonic and adult-onset diabetics have in common pancreatic beta-cell dysfunction, abnormally high serum insulin levels, and possibly defective hormone-receptor interactions. Whether these factors contribute to the altered blood-iris barrier and iris neovascular tufts in these groups is uncertain, but a correlation is suggested because the myotonic with the highest insulin level also had the most prominent tufts. Hyperinsulinemia and ocular hypotony are associated with neovascular tufts.

Adolescent↗
PubMed1985

Ocular neovascularization. Tissue culture studies.

The proliferative activity of a number of intraocular fluids, bovine retinal extract, and normal serum (from humans and cynomolgus monkeys) was investigated by in vitro tissue culture studies, with the use of tritiated thymidine incorporation by the cultured endothelial cells of human umbilical veins. There was increased tritiated thymidine incorporation by (1) the aqueous, vitreous, and intraocular fluid (IOF) (which filled the eye after lensectomy and vitrectomy) removed from cynomolgus monkey eyes with iris neovascularization or with neovascular glaucoma (NVG) that developed after experimental retinal vein occlusion, (2) by aqueous and vitreous removed from human eyes with NVG or proliferative diabetic retinopathy; (3) by the serum, and (4) by the bovine retinal extract. However, tritiated thymidine incorporation was not increased by the normal aqueous, vitreous, or IOF.

Animals↗
PubMed1985

Scanning electron microscopy of the ocular vasculature in retinopathy of prematurity.

Clinicoanatomopathologic correlations in a case of the retinopathy of prematurity are reported. A premature infant delivered at 28 weeks of gestation (weight, 900 g) was hospitalized for a number of health problems, including bronchopulmonary dysplasia and respiratory distress syndrome. Ophthalmic examination, at the age of 5 months, disclosed stage 1B retinopathy of prematurity. The patient died at the age of 161 days; both eyes were taken for scanning electron microscopy and histopathologic studies. Scanning electron microscopy findings included absence of retinal capillaries, anterior uveal neovascularization originating from the venous side, and a coincidental typical coloboma of the optic nerve and choriocapillaris. Histopathologic findings confirmed iris stromal neovascularization, showed retinal neovascularization with proliferation into the vitreous and avascular areas between the midperiphery and ora serrata.

Blood Vessels↗
PubMed1985

The histopathology of corneal neovascularization. Inhibitor effects.

With the use of a previously described model of corneal neovascularization induced by thermal cautery, we examined the effects of inhibitors on both the incidence of corneal neovascularization and the degree of inflammatory cell response. Three known inhibitors of corneal neovascularization, 1% prednisolone acetate, indomethacin, and 0.3% flurbiprofen, were studied and the results were compared with those in saline-treated controls. As expected, corneal neovascularization, preceded by conjunctival and corneal polymorphonuclear leukocyte (PMNL) infiltration, occurred in all control animals. Corneal neovascularization did not occur in any of the inhibitor-treated eyes. Histopathologically, both conjunctival and corneal PMNL counts in the treated eyes were markedly reduced compared with controls. These findings are consistent with the hypothesis that inflammatory cells, particularly PMNLs, are closely associated with the initiation of corneal neovascularization.

Animals↗
PubMed1985

Simulated treatment of recurrent choroidal neovascularization in primate retina. Comparative histopathologic findings.

We simulated the treatment of recurrent choroidal neovascular membranes (CNVM) by applying two courses of laser treatment to monkey retinas. Argon green, argon blue-green, and krypton red lasers (KRLs) were used in juxtafoveal, papillomacular bundle, and nonmacular areas. The effects were examined clinically and histopathologically. Results of once-treated control eyes were consistent with those of previous studies. Repeat treatment, however, resulted in full-thickness retinal destruction or necrosis with all laser modalities and in all fundus locations. These results are consistent with the absorptive characteristics of xanthophyll and melanin and suggest only limited advantages to the KRL when treatment of recurrent CNVM is performed in a previously treated area of the fundus. However, treatment of recurrent CNVM is still probably most successful with a KRL, because recurrent CNVM is usually at a border of a photocoagulation scar, where the retina is still untreated, and because histologic studies have demonstrated inner retinal sparing with a KRL in juxtafoveal areas.

Animals↗
PubMed1985

Choroidal reaction and vascular repair after chorioretinal photocoagulation with the free-running neodymium-YAG laser.

The morphologic effects of the neodymium-YAG laser working in the free-running mode on the choroid of pigmented rabbit eyes have been studied by electron microscopy. Two different mechanisms closing the choroidal vessels were found. The larger vessels of the vascular lamina were closed by platelet aggregation, while within the choriocapillaries a network of fibrin could be observed. The endothelial cells of the vessels were found to be damaged in capillaries as well as in the larger vessels. Within the irradiated area, a revascularization process takes place, expanding from the border towards the center. The process begins a few days after treatment and continues for more than four months. The process of neovascularization is described in detail. Beside fibroblasts, cells could be found that were active in producing elastic fibers.

Animals↗
PubMed1985

Effects of intravitreal administration of steroids on experimental subretinal neovascularization in the subhuman primate.

To elucidate the role of inflammation in the occurrence of experimental subretinal neovascularization caused by high-intensity laser photocoagulation, we investigated the effects of vitreal infusion of steroids on laser lesions in a primate model. Dexamethasone, with or without triamcinolone, was infused continuously for two weeks through an indwelling cannula system. The animals were followed up clinically for up to eight weeks. The frequency of subretinal neovascularization in the steroid-treated animals was significantly lower than that in a control group of untreated animals. Although steroids have multiple effects, these results suggest that the inflammatory response, possibly macrophage infiltration, may plan an important role in the occurrence of subretinal neovascularization in our experimental model.

Animals↗
PubMed1985

Lipid keratopathy in rabbits. An animal model system.

Rabbits rendered hypercholesterolemic on a high cholesterol diet while subjected to corneal suture placement to induce neovascularization made useful models for qualitatively and quantitatively studying lipid keratopathy. Forty rabbit eyes were subjected to placement of four sutures located between 1 and 4 mm from the limbus. The neovasculature grew at a constant rate of 0.24 mm/day, unaffected by serum cholesterol levels. Rabbits fed cholesterol prior to surgery were the earliest to display lipid keratopathy, followed by those who began cholesterol feedings on the day of surgery, and last by rabbits who began receiving high cholesterol food seven days following suture placement. A description of the corneal neovascularization process and histopathological and biochemical analyses of the induced lipid keratopathy are presented.

Animals↗
PubMed1985

Clinical photocoagulation with the organic dye laser. A preliminary communication.

Clinical research utilizing the yellow, orange, and red wavelengths of the liquid organic dye laser has demonstrated that this laser may be successfully used for photocoagulation of certain ophthalmic defects. The advantage of the dye laser as a photocoagulation source is its capability to produce monochromatic wavelengths at relatively high output powers through a large range of the visible spectrum. Therefore, a target tissue can be coagulated with minimal transmittal of laser energy through the ocular media, by the selection of a wavelength that would be most highly absorbed by that tissue. The dye laser, as a system that permits transspectral photocoagulation, should prove valuable in the treatment of ocular disease.

Aging↗
PubMed1985

Circinate-pattern interstitial keratopathy in daily wear soft contact lens wearers.

Three male and two female patients (aged 16 to 22 years) developed bilateral deep corneal stromal vascularization and circinate-pattern lipid exudation resembling interstitial keratitis after wearing adequately fitting hydrogel daily wear soft contact lenses comfortably for periods of ten to 24 months. The circinate pattern consisted of lipid deposition in circular distribution either parallel to the limbus or around a deep stromal blood vessel. All had negative serologic test results for syphilis. The cause of these changes is uncertain.

Adolescent↗