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At least 55 records · Page 3Linked to original sources
PubMed2000

A preliminary study of photodynamic therapy using verteporfin for choroidal neovascularization in pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes.

OBJECTIVE: To evaluate short-term safety and the effects on visual acuity and fluorescein angiography of single or multiple sessions of photodynamic therapy with verteporfin for choroidal neovascularization (CNV) not related to age-related macular degeneration (AMD), including pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. DESIGN: A nonrandomized, multicenter, open-label, dose-escalation phase 1 and 2 clinical trial. SETTING: Four ophthalmic centers in Europe and North America providing retinal care. PARTICIPANTS: Thirteen patients with subfoveal CNV due to pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, or idiopathic causes. METHODS: Standardized protocol refraction, visual acuity testing, ophthalmic examinations, color photographs, and fluorescein angiograms were used to evaluate the results of photodynamic therapy treatments with verteporfin. Follow-up ranged from 12 weeks for patients who were treated once to 43 weeks for patients who were treated up to 4 times. RESULTS: Verteporfin therapy was well tolerated in patients with CNV not related to AMD. No deterioration in visual acuity was observed; most patients gained at least 1 line of vision. Reduction in the size of leakage area from classic CNV was noted in all patients as early as 1 week after verteporfin therapy, with complete absence of leakage from classic CNV in almost half of the patients. Improvement in visual acuity after verteporfin therapy was greatest (+6, +8, and +9 lines) in 3 patients with relatively poor initial visual acuity (between 20/200 and 20/800). Up to 4 treatments were found to have short-term safety even with retreatment intervals as short as 4 weeks. CONCLUSIONS: Treatment of CNV not related to AMD with verteporfin therapy achieves short-term cessation of fluorescein leakage from CNV in a small number of patients without loss of vision. Further randomized clinical trials including a larger number of patients are under way to confirm whether verteporfin therapy is beneficial for subfoveal CNV not related to AMD.

Adult↗
PubMed2003

Factors associated with the development of chorioretinal atrophy around choroidal neovascularization in pathologic myopia.

PURPOSE: To examine the influencing factors on the development of chorioretinal atrophy, which is the main cause of long-term visual decrease in myopic choroidal neovascularization (CNV), in a large series of highly myopic patients. METHODS: Sixty-five patients (81 eyes) with myopic CNV were studied retrospectively. The influence of the patient's age, refractive error, axial length, visual acuity at onset of CNV, size of CNV, and grade of myopic retinopathy on the extent of chorioretinal atrophy more than 3 years after CNV onset was investigated by means of multiple linear regression analysis. RESULTS: Seventy-seven of 81 eyes (95.1%) developed chorioretinal atrophy around myopic CNV during the follow-up period. Multiple linear regression revealed that age was the most influencing factor for the development of chorioretinal atrophy in all the subjects. When we divided the subjects into two groups according to their age, however, CNV size was the only factor to influence the development of chorioretinal atrophy in the patients younger than 40 years, whereas age was still the only influencing factor in those older than 40 years. CONCLUSIONS: The factors influencing the development of chorioretinal atrophy differ according to patient age. Local factors, such as CNV size, determine the tendency to develop chorioretinal atrophy in young patients. Systemic factors, such as patient age, play a greater part in older subjects.

Atrophy↗
PubMedDate not supplied

Antiangiogenesis and anticancer efficacy of TA138, a novel alphavbeta3 antagonist.

BACKGROUND: Angiogenesis is a complex process involving endothelial cell migration, proliferation, invasion, and tube formation. Inhibition of these processes might have implications in various angiogenesis-mediated disorders. MATERIALS AND METHODS: The antiangiogenic efficacy of the novel alphavbeta3 antagonist TA138 was examined using in vivo and in vitro model systems. RESULTS: The in vitro studies demonstrated the ability of TA138 and RP747 (conjugated TA138) to inhibit endothelial cell migration toward vitronectin, with an IC50=0.04 and 0.045 microM, respectively. Furthermore, utilizing the chick chorioallantoic membrane models, TA138 inhibited basic fibroblast growth factor-induced neovascularization. CONCLUSION: TA138 might be a useful tool for the inhibition of angiogenesis associated with human tumor growth, or other pathological neovascularization processes. RP747 demonstrated antitumor efficacy in 1 spontaneous tumor model (c-neu oncomouse model, alphavbeta3 positive cells) and in 1 xenograft model (HCT116 human tumor colon carcinoma, alphavbeta3 negative cells) injected subcutaneously into nude mice.

Adenocarcinoma↗
PubMed2005

Soluble forms of EphrinB2 and EphB4 reduce retinal neovascularization in a model of proliferative retinopathy.

PURPOSE: Ephrin ligands and their Eph receptors are key regulators of endothelial cell (EC) proliferation, migration, adhesion, and repulsion during mammalian vascular development. The hypothesis was that these molecules also play a role in pathologic neovascularization (NV) in the mouse model of oxygen-induced retinopathy. METHODS: C57BL/6 mice at postnatal day (P)7 were exposed to 75% oxygen (O(2)) for 5 days (until P12) and allowed to recover in room air to induce retinal NV. Retinas from unexposed and hyperoxia-exposed mice between P7 to P24 were analyzed specifically for EphrinB2 and EphB4 transcript expression by RT-PCR. Phospho-Eph (p-Eph) receptor was evaluated during active EC proliferation at P15 and P17 by immunohistology. Some hyperoxia-exposed mice had one eye injected intravitreally with 150 ng/1.5 microL of soluble EphrinB2/Fc or EphB4/Fc chimeras during transition from high O(2) to room air (P12) and injected again on P14. Contralateral eyes were injected with human IgG as the control. Preretinal nuclei and retinal blood vessels were quantified at peak disease (P17). RESULTS: EphrinB2 mRNA was constitutively expressed in the developing retina and was unchanged by hyperoxia. In contrast, EphB4 mRNA expression was modulated during normal retinal development and was altered by hyperoxia. Furthermore, p-Eph was detected in developing preretinal tufts, thus implying that Ephrin/Eph signaling system is active in this experimental model. Intravitreal injection of soluble versions of these molecules significantly reduced pathologic neovascularization. The number of preretinal nuclei in hyperoxia-treated mice was reduced by 66% (P < 0.05) in EphrinB2-injected eyes, whereas EphB4 treatment yielded a 69% reduction (P < 0.05), compared with control injections. Intraretinal vessel development was not altered by the injections. CONCLUSIONS: These results support the hypothesis that endogenous EphrinB2 and EphB4 are regulators of retinal NV during oxygen-induced retinopathy and may be useful targets for therapeutic intervention.

Animals↗
PubMed2005

Endothelial progenitor cells for vasculogenesis.

Postnatal vasculogenesis is considered to be involved in neovascularization of adult tissues, because bone marrow-derived endothelial progenitor cells (EPCs) were isolated from circulating mononuclear cells in peripheral blood and were shown to incorporate into sites of physiological and pathological neovascularization and to differentiate into mature endothelial cells. EPCs might have an attractive potential therapeutic application for cardiovascular ischemic diseases as a novel cell-based strategy mainly via a vasculogenesis mechanism.

Animals↗
PubMed2005

Choroidal neovascularization in pathologic myopia: three-year results after photodynamic therapy.

PURPOSE: To examine whether the encouraging functional results one year after photodynamic therapy (PDT) can be maintained up to three years. DESIGN: Prospective interventional case series. METHODS: Highly myopic eyes that had been treated with PDT for subfoveal choroidal neovascularization and had been observed at least 36 months were included. Distance acuity (Early Treatment of Diabetic Retinopathy charts), reading acuity (Jaeger charts), 10-degree static threshold perimetry, fluorescein angiography, and optical coherence tomography were performed. The main outcome measures were the differences of the values among the baseline and the month 12 and the month 36 examinations. RESULTS: Twenty eyes of 18 patients were included: 15 patients were female, and 3 patients were male. The average age was 64 years (range, 36 to 85 years). The mean distance acuity was 43 letters at baseline and 53 letters after 12 months and after 36 months. The mean reading acuity changed from mean J10.8 to mean J8.1 after 12 months and to mean J9.85 after 3 years. The mean defect decreased from mean 13.5 dB at baseline to mean 12.5 dB after 12 months and mean 11.2 dB after 36 months. The maximum retinal thickness decreased from mean 360 mum at baseline to mean 259 mum after one year and mean 238 mum after 36 months. CONCLUSION: Distance acuity and central visual field showed stabilization after the month 12 examination up to the month 36 examination. The reading acuity decreased between the month 12 and the month 36 examinations, which might be related to an increase of retinal atrophy.

Adult↗
PubMed2001

Engineering and characterization of functional human microvessels in immunodeficient mice.

SUMMARY: Current model systems used to investigate angiogenesis in vivo rely on the interpretation of results obtained with nonhuman endothelial cells. Recent advances in tissue engineering and molecular biology suggest the possibility of engineering human microvessels in vivo. Here we show that human dermal microvascular endothelial cells (HDMEC) transplanted into severe combined immunodeficient (SCID) mice on biodegradable polymer matrices differentiate into functional human microvessels that anastomose with the mouse vasculature. HDMEC were stably transduced with Flag epitope or alkaline phosphatase to confirm the human origin of the microvessels. Endothelial cells appeared dispersed throughout the sponge 1 day after transplantation, became organized into empty tubular structures by Day 5, and differentiated into functional microvessels within 7 to 10 days. Human microvessels in SCID mice expressed the physiological markers of angiogenesis: CD31, CD34, vascular cellular adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). Human endothelial cells became invested by perivascular smooth muscle alpha-actin-expressing mouse cells 21 days after implantation. This model was used previously to demonstrate that overexpression of the antiapoptotic protein Bcl-2 in HDMEC enhances neovascularization, and that apoptotic disruption of tumor microvessels is associated with apoptosis of surrounding tumor cells. The proposed SCID mouse model of human angiogenesis is ideally suited for the study of the physiology of microvessel development, pathologic neovascular responses such as tumor angiogenesis, and for the development and investigation of strategies designed to enhance the neovascularization of engineered human tissues and organs.

Absorbable Implants↗
PubMed1990

[Pathophysiology of intraocular neovascularization].

The pathology of intraocular neovascularization was studied in human and animal eyes by means of electron microscopy and histochemistry, and also by tissue culture of bovine retinal small vessels. The newly formed vessels in the vitreous obtained at the time of vitrectomy from the eyes with proliferative diabetic retinopathy and retinal vein occlusion lacked tight junction and formed fenestration in the endothelial cells. When 1 microgram of the basic fibroblast growth factor (b-FGF) enveloped in ethylene vinyl acetate copolymer was implanted into the vitreous of monkey eyes, new vessels were formed in the iris in all eyes and in the vitreous in 12 eyes out of 14 experimental eyes. The origins of new vessels were the iris vessels in the iris, and both stromal vessels of the ciliary body and retinal vessels in the vitreous. These vessels showed fenestration in the endothelial cells. The activity of the lysosomal enzyme detected by acid phosphatase increased in the epithelial layer of the ciliary body. The new vessels in the vitreous of rabbits were seen in 9 out of 10 eyes when b-FGF was implanted in the vitreous with an intravitreal injection of amino adipic acid solution (1 mg in 0.2 ml of physical saline), although none of the 8 eyes formed new vessels when sodium iodate was injected intravenously after implantation of b-FGF with aminoadipic acid. Corneal neovascularization was formed by implantation of 250 ng of b-FGF into the corneal micropockets of the guinea pigs, and regressed after the b-FGF was removed. The endothelial budding and protrusion were frequently seen during the course of neovascularization. Immunohistochemical detections showed positive stainings for fibronectin in most front-end lesions, for laminin and type 4 collagen associated with the endothelial cells, and for factor VIII only on the endothelial cells which formed the vascular lumen. The acid phosphatase activity was detected on the leucocytes infiltrating in the corneal stroma. In the course of regression of corneal neovascularization, initial pathological change was thrombus formation followed by disappearance of endothelial cells, although the basement membrane of the endothelial cells remained. Fibronectin reduced its activity in the early stage of regression, laminin and type 4 collagen remained even after the vascular lumen had subsided, and factor VIII was stained in a geographically irregular manner. Migrating activity of the cultured-bovine retinal small vessels was accelerated by fibronectin and fetal bovine serum.

Animals↗
PubMed2002

Angiopoietin-2 plays an important role in retinal angiogenesis.

Angiopoietin 2 (Ang2) expression in the retina is increased during physiologic and pathologic neovascularization suggesting that it may be involved. In this study, we used Ang2-deficient mice to test that hypothesis. Mice deficient in Ang2 showed delayed and incomplete development of the superficial vascular bed of the retina, which develops primarily by vasculogenesis, and complete absence of the intermediate and deep vascular beds which develop by angiogenesis. In addition to incomplete retinal vascular development, Ang2-deficient mice showed lack of regression of the hyaloid vasculature, resulting in a phenotype that mimics infants with persistent fetal vasculature (PFV), a relatively common congenital abnormality. Exposure to high levels of oxygen resulted in partial regression of the retinal vessels, indicating that oxygen-induced regression of retinal vessels does not require Ang2. When these oxygen-exposed mice with few retinal vessels were moved to room air, there was no ischemia-induced retinal neovascularization. These data support the hypothesis that Ang2 plays a critical role in physiologic and pathologic angiogenesis, and physiologic, but not oxygen-induced vascular regression. The data also suggest that infants with PFV should be examined for genetic modifications that would be expected to cause perturbations in Tie2 signaling.

Angiopoietin-2↗
PubMed1999

VEGF and vascular fusion: implications for normal and pathological vessels.

The avian embryo is well suited for the study of blood vessel morphogenesis. This is especially true of investigations that focus on the de novo formation of blood vessels from mesoderm, a process referred to as vasculogenesis. To examine the cellular and molecular mechanisms regulating vasculogenesis, we developed a bioassay that employs intact avian embryos. Among the many bioactive molecules we have examined, vascular epithelial growth factor (VEGF) stands out for its ability to affect vasculogenesis. Using the whole-embryo assay, we discovered that VEGF induces a vascular malformation we refer to as hyperfusion. Our studies showed that microinjection of recombinant VEGF165 converted the normally discrete network of embryonic blood vessels into enlarged endothelial sinuses. Depending on the amount of VEGF injected and the time of postinjection incubation, the misbehavior of the primordial endothelial cells can become so exaggerated that for all practical purposes the embryo contains a single enormous vascular sinus; all normal vessels are subsumed into a composite vascular structure. This morphology is reminiscent of the abnormal vascular sinuses characteristic of certain neovascular pathologies. (J Histochem Cytochem 47:1351-1355, 1999)

Animals↗
PubMed1993

Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity.

Thrombospondin-1 (TSP1) is a large modular matrix protein containing three identical disulfide-linked 180-kD chains that inhibits neovascularization in vivo (Good et al., 1990). To determine which of the structural motifs present in the 180-kD TSP1 polypeptide mediate the anti-angiogenic activity, a series of protease-generated fragments were tested using several in vitro and in vivo assays that reflect angiogenic activity. The majority of the anti-angiogenic activity of TSP1 resides in the central 70-kD stalk region which alone could block neovascularization induced by bFGF in the rat cornea in vivo and inhibit both migration in a modified Boyden chamber and [3H]thymidine incorporation stimulated by bFGF in cultured capillary endothelial cells. Although TSP1 has been shown to bind active TGF beta 1, this cytokine could not account for the inhibitory effects of the stalk region of TSP1 on cultured endothelial cells. Peptides and truncated molecules were used to further localize inhibitory activity to two domains of the central stalk, the procollagen homology region and the properdin-like type 1 repeats. Trimeric recombinant TSP1 containing NH2-terminal sequences truncated after the procollagen-like module inhibited endothelial cell migration in vitro and corneal neovascularization in vivo whereas trimeric molecules truncated before this domain were inactive as was the NH2-terminal heparin-binding domain that is present in both recombinant molecules. A series of peptides from the procollagen-like region, the smallest of which consisted of residues 303-309 of TSP1, inhibited angiogenesis in vivo in the rat cornea and the migration of endothelial cells in vitro. A 19-residue peptide containing these sequences blocked vessel formation in the granulation tissue invading a polyvinyl sponge implanted into the mouse. Nineteen residue peptides derived from two of the three type 1 repeats present in the intact TSP1 molecule blocked neovascularization in vivo in the rat cornea and inhibited the migration of cultured endothelial cells with ED50's of 0.6-7 microM. One of these peptides, containing residues 481-499 of TSP1, also inhibited vessel formation in granulation tissue invading sponges in vivo. These results suggest that the large TSP1 molecule employs at least two different structural domains and perhaps two different mechanisms to accomplish a single physiological function, the inhibition of neovascularization. The definition of short peptides from each of these domains that are able to block the angiogenic process may be of use in designing targeted inhibitors of the pathological neovascularization that underlies many diseases.

Amino Acid Sequence↗
PubMed2004

Role of eNOS in neovascularization: NO for endothelial progenitor cells.

Nitric oxide (NO) is a gaseous molecule with an astonishingly wide range of physiological and pathophysiological activities, including the regulation of vessel tone and angiogenesis in wound healing, inflammation, ischaemic cardiovascular diseases and malignant diseases. Recent data have revealed the predominant role of endothelial nitric oxide synthase (eNOS), an endothelial-cell-specific isoform of NO producing enzyme, in both angiogenesis (the development of new blood vessels derived from existing vessels) and vasculogenesis (blood vessel formation de novo from progenitor cells). In addition, successes in gene therapy, together with the recent development of an eNOS-specific inhibitor, suggest that the modulation of eNOS might be a potent new strategy for the control of pathological neovascularization.

Animals↗
PubMed1998

CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth.

CYR61 is a secreted, cysteine-rich, heparin-binding protein encoded by a growth factor-inducible immediate-early gene. Acting as an extracellular, matrix-associated signaling molecule, CYR61 promotes the adhesion of endothelial cells through interaction with the integrin alphaVbeta3 and augments growth factor-induced DNA synthesis in the same cell type. In this study, we show that purified CYR61 stimulates directed migration of human microvascular endothelial cells in culture through an alphaV beta3-dependent pathway and induces neovascularization in rat corneas. Both the chemotactic and angiogenic activities of CYR61 can be blocked by specific anti-CYR61 antibodies. Whereas most human tumor-derived cell lines tested express CYR61, the gastric adenocarcinoma cell line RF-1 does not. Expression of the CYR61 cDNA under the regulation of a constitutive promoter in RF-1 cells significantly enhances the tumorigenicity of these cells as measured by growth in immunodeficient mice, resulting in tumors that are larger and more vascularized than those produced by control RF-1 cells. Taken together, these results identify CYR61 as an angiogenic inducer that can promote tumor growth and vascularization; the results also suggest potential roles for CYR61 in physiologic and pathologic neovascularization.

Animals↗
PubMed2003

Multistep nature of microvascular recruitment of ex vivo-expanded embryonic endothelial progenitor cells during tumor angiogenesis.

Tissue neovascularization involves recruitment of circulating endothelial progenitor cells that originate in the bone marrow. Here, we show that a class of embryonic endothelial progenitor cells (Tie-2+, c-Kit+, Sca-1+, and Flk-1-/low), which were isolated at E7.5 of mouse development at the onset of vasculogenesis, retain their ability to contribute to tumor angiogenesis in the adult. Using intravital fluorescence videomicroscopy, we further defined the multistep process of embryonic endothelial progenitor cell (eEPC) homing and incorporation. Circulating eEPCs are specifically arrested in "hot spots" within the tumor microvasculature, extravasate into the interstitium, form multicellular clusters, and incorporate into functional vascular networks. Expression analysis and in vivo blocking experiments provide evidence that the initial cell arrest of eEPC homing is mediated by E- and P-selectin and P-selectin glycoprotein ligand 1. This paper provides the first in vivo insights into the mechanisms of endothelial progenitor cell recruitment and, thus, indicates novel ways to interfere with pathological neovascularization.

Animals↗
PubMed1981

Pathologic myopia and choroidal neovascularization.

In 14 of 27 eyes with choroidal neovascular membranes associated with severe myopia, visual acuity deteriorated two or more lines on the Snellen chart. Twelve of the 27 eyes became legally blind. Final visual acuity may be related to the position of the neovascular membrane within the posterior pole. Four of the eight eyes with new vessels outside of the foveal avascular zone had follow-up visual acuities of 6/12 (20/40) or better. Only one of five eyes with new vessels extending to the edge of the avascular zone had a final visual acuity of 6/12 (20/40) or better. Three of 14 eyes with a neovascular membrane beneath the foveal avascular zone had visual acuities of 6/12 (20/40) or better. Neovascularization associated with severe myopia clearly jeopardizes central visual acuity. Laser photocoagulation therapy may be useful in treating neovascular membranes outside the foveal avascular zone or extending to the edge of the perifoveal capillary network. A larger prospective study is needed to determine the guidelines for and efficacy of such treatment for patients with severe myopia who develop choroidal neovascularization.

Adult↗