[Angiogenesis in ophthalmology. A theme with a future].
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Adult↗
Biomedical subjects
A M Joussen
Publications and source records attributed to A M Joussen.
[Pigmented retinopathy as a presenting sign of mitochondrial encephalomyopathy without external ophthalmoplegia].
BACKGROUND: Mitochondrial encephalomyopathies result from deletions in the nuclear or mitochondrial (mt) DNA. Deletions in the mtDNA are often sporadic. Mitochondriopathies are commonly associated with chronic progessive external ophthalmoplegia (CPEO). Here we describe a patient with a structural mtDNA aberration whose presenting sign was impaired visual acuity in the presence of a pigmented retinopathy but lack of impaired ocular motility. PATIENT: A 7-year-old girl presented with impaired visual acuity (0.4 OD and 0.5 OS), coarse hyperpigmentation of the posterior pole and diffuse hyperpigmentation with irregular depigmentation in the periphery. Scotopic and photopic as well as multifocal ERG were abnormal. Further symptoms included an incomplete inner ear deafness, ataxia, lapses of coordination and an intention tremor. Compared with her twin sister, the patient's speech was less modulated and slower. MRI scanning disclosed symmetric changes of density in the basal ganglia and nucleus dentatus as well as in the brainstem. ECG yielded no evidence of an AV-node block. Molecular biological analysis showed a structural rearrangement of the mtDNA. CONCLUSIONS: Mitochondrial encephalomyopathies in early ages may present with pronounced retinal changes in the absence of external ophthalmoplegia.Therefore, it appears prudent to include a neuropediatric evaluation as well as a mutation screening of the mtDNA in the evaluation of pediatric patients with diffuse non-specific pigmented retinopathies.
Blotting, Southern↗
[The molecular mechanisms of neovascular age-related macular degeneration].
Age-related macular degeneration is the leading cause of irreversible vision loss in industrialized countries. While early forms of this disease with drusen and focal pigment alterations generally do not lead to relevant functional limitations, later forms of the disease, either through atrophy or choroidal neovascularization, are associated with significant visual impairment. A significant increase in knowledge about the molecular mechanisms of new vessel formation from the choriocapillaries has occurred over the past few years. This has already allowed for the clinical testing of pharmacological agents which inhibit the formation of new vessels in AMD. This article describes current research in the pathophysiology of choroidal neovascularization secondary to age-related macular degeneration.
Aged↗
[Molecular mechanisms of vasculogenesis and angiogenesis. What regulates vascular growth?].
The basic mechanisms governing how endothelial cells, periendothelial cells, matrix molecules and blood constituents interact with each other are discussed. The many insights gained from this basic knowledge are being extended to further understand physiological and pathological features of vascular sprouting and maintenance. Understanding these basic principles that drive angiogenesis and vasculogenesis will lead to a more specific therapy of many disorders in ophthalmology and other fields, such as arteriosclerosis, tumor growth, myocardial ischemia and tissue repair.
Adult↗
[Diabetic retinopathy. Pathophysiology and therapy of hypoxia-induced inflammation].
Diabetic retinopathy is the most common chronic microvascular complication associated with diabetes mellitus. The development of diabetic retinopathy is a consequence of metabolic dysregulation. Hyperglycemia is a critical factor which is involved in basement membrane thickening, loss of pericytes and endothelial cells, and retinal capillary nonperfusion. We review the molecular basis of diabetic retinopathy and maculopathy and elaborate the role of growth factors and cytokines in the development of diabetic vascular alterations, their specific influence on the cellular interaction between retinal endothelial cells and pericytes, and the role of intravascular blood components.
Animals↗
[Pathogenesis of choroidal neovascularization. Old concepts, new questions].
Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world but the pathogenesis remains poorly understood. Malfunction of the retinal pigment epithelium (RPE) plays a central role in the disease and leads to either choriodal atrophy or proliferation. This article reviews the current concepts of the development of choriodal atrophy and neovascularisation. Furthermore, available animal models and potential therapeutical targets are discussed.
Age Factors↗
[Angiogenesis in ophthalmology. Part 2: Current considerations on the pathogenesis of diabetic and hypoxia-induced retinopathy].
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Animals↗
Retinectomy for treatment of intractable glaucoma: long term results.
AIM: To report long term efficacy and complications of retinectomy as an intraocular pressure lowering procedure for intractable glaucoma. METHODS: This was a consecutive interventional case series. In 44 consecutive eyes (39 patients, 22 men and 17 women) retinectomy was performed to lower the intraocular pressure (IOP) in patients with uncontrolled IOP (>35 mm Hg for more than 4 months) despite conventional filtering surgery and drug treatment. Pars plana vitrectomy was performed and the peripheral retina was surgically excised to various degrees. The procedure was concluded by an intraocular gas tamponade of 20% C(3)F(8). Included were patients with neovascular glaucoma (12 eyes), infantile and juvenile glaucoma (three eyes), secondary glaucoma due to aphakia (13 eyes), severe ocular trauma (seven eyes), uveitis (seven eyes), and glaucoma in Ehlers-Danlos syndrome (two). RESULTS: All patients underwent successful surgical retinectomy. All patients were followed for 5 years. Mean postoperative IOP after 4 years was 15.7 (SD 9.4) mm Hg, representing a decrease of IOP by 61% compared to the preoperative level (41.2 (9.4) mm Hg). In 52.3% of eyes long term regulation of IOP could be achieved without complications. Retinectomy was least effective in neovascular glaucoma because of central retinal vein occlusion (CRVO). Eyes with glaucoma secondary to uveitis showed a tendency towards low IOP levels with subsequent phthisis bulbi. The initial visual acuity of all patients was lower than 20/50 (mean 1.8 (0.8) logMAR) in the treated eye. Final visual acuity was 2.3 (0.6) logMAR. 21 out of 44 cases developed retinal complications (retinal detachment or proliferative vitreoretinopathy (PVR)) after surgery, requiring silicone tamponade in 11 eyes (52%) either for persistent low IOP or for PVR. Nine eyes developed phthisis, seven of which were enucleated during the follow up. CONCLUSIONS: Long term results after retinectomy demonstrate its efficacy in otherwise intractable glaucoma. Efficacy and safety of retinectomy are dependent on the underlying disease.
Adult↗
Effect of antiangiogenic therapy on slowly growing, poorly vascularized tumors in mice.
BACKGROUND: Angiogenesis is essential for tumor growth and progression. Therefore, inhibition of angiogenesis is being studied as a new anticancer therapy. Because cytotoxic chemotherapy is more effective on rapidly growing tumors than on slowly growing tumors, it has been assumed that antiangiogenic therapy will also be effective only on rapidly growing, highly vascularized tumors. We compared the effects of two angiogenesis inhibitors, TNP-470 and angiostatin, on slowly growing, poorly vascularized and rapidly growing, highly vascularized human tumors in mice. METHODS: Slowly growing (RT-4) and rapidly growing (MGH-U1) human bladder carcinoma cell lines were grown in severe combined immunodeficiency mice. Established tumors were treated with one of the two angiogenesis inhibitors. Tumor volumes, vascularity, and proliferation indices were determined. The in vitro effects of TNP-470 and of angiostatin on the proliferation of RT-4 and MGH-U1 cells were also investigated. All statistical tests were two-sided. RESULTS: RT-4 and MGH-U1 tumor growth was statistically significantly inhibited by both angiogenesis inhibitors (P<.001). Both inhibitors decreased the blood vessel density in both tumor types but did not alter the in vivo proliferation indices of the tumors. TNP-470, but not angiostatin, marginally decreased the in vitro proliferation of MGH-U1 cells. CONCLUSION: Slowly growing, poorly vascularized tumors in animal models respond as well as rapidly growing, highly vascularized tumors to therapy with the angiogenesis inhibitors TNP-470 and angiostatin.
Angiogenesis Inhibitors↗
Low-dose-rate ionizing irradiation for inhibition of secondary cataract formation.
INTRODUCTION: Secondary cataract formation limits visual function after cataract surgery. Various experimental methods utilizing the pharmacologic inhibition of lens epithelial cell proliferation have been proposed. However, diffusion into the anterior chamber may lead to damage of corneal endothelial cells. This study evaluated the inhibition of lens epithelial cell proliferation with a capsular bag ring, labeled with a beta-emitting radioisotope. METHODS AND MATERIALS: In vitro studies using rabbit lens epithelial cells were performed to investigate the dose-dependent effect of irradiation. Based on these results, P-32-labeled PMMA rings were implanted into the capsular bag of NZW rabbits in vivo after phacoemulsification. Animals were examined for development of posterior capsule opacification over a period of 12 weeks following surgery. Radiation damage to the surrounding ocular tissue was subsequently analyzed in histologic sections using TUNEL assay and proliferation marker. RESULTS: Irradiation of lens epithelial cells in vitro with >5 Gy resulted in a dose-dependent decrease in the number of cells. BrdU testing demonstrated a near complete inhibition of cell proliferation. In vivo, implantation of P-32-labeled PMMA rings led to inhibition of epithelial cell proliferation and secondary cataract formation but was not able to fully inhibit aberrant differentiation of some remaining cells. Histologic examination showed no evidence of radiation damage of the ciliary body or the corneal endothelium. CONCLUSIONS: Low-dose beta irradiation exhibits the potential for inhibition of lens epithelial cell proliferation both in vitro and in vivo. Further investigation of various nuclides and their radiation profiles is needed to optimize the prevention of posterior capsule opacification due to epithelial cell proliferation.
Animals↗
[Diabetic maculopathy. Etiological mechanisms and possible treatment approaches].
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Capillary Permeability↗
[Possibilities of broad spectrum analysis of gene expression patterns with cDNA arrays].
BACKGROUND: Our knowledge about the molecular and genomic background of diseases has expanded dramatically in the recent past and cDNA microarrays now provide the opportunity to simultaneously analyse the expression of thousands of genes. This could pave the way towards a systematic exploration of the pathogenetic principle of ophthalmological diseases which could lead to the identification of key disease-specific molecules that will be useful as diagnostic marker or serve as therapeutic targets. MATERIALS AND METHODS: Various strategies for cDNA microarray analysis are reviewed, including different commercially available arrays (microarrays on glass and arrays on nylon filters) as well as methods for analysing the unprecedented large amounts of data from a single experiment. Possible applications for research and clinical applications in ophthalmology are discussed. RESULTS: The cDNA microarray-based technology allows the rapid and cost-effective screening of gene expression without a priori knowledge about which gene might be of interest. Here, we discuss how the analysis of gene expression as whole profiles instead of the conventional focus on an individual gene may offer new insights into the fundamental nature of the pathogenesis of complex diseases using the example of early diabetic retinopathy. CONCLUSION: To date, the gene-array technology is still largely a laboratory procedure and has not yet been used in the clinical setting. However, in clinically oriented basic research, it will allow a more encompassing analysis of disease processes and thus lead to the identification of important diagnostic tools and potential drug targets in ophthalmological diseases.
Diabetic Retinopathy↗
Vascular plasticity--the role of the angiopoietins in modulating ocular angiogenesis.
Most of the blinding diseases, such as diabetic retinopathy, age-related macular degeneration, neovascular glaucoma or trachoma, are related to an aberrant angiogenic response. Common pathological features are ischaemia and increased vascular permeability, in turn leading to neovascularization or atrophy. Recent effort has led to the identification of several factors, such as the angiopoietin-Tie system, which are operative in the control of vasculogenesis and angiogenesis. The aim of this commentary is to summarize briefly the current knowledge about molecular mechanisms involved in the regulation of vascular integrity with special emphasis on the angiopoietins.
Angiopoietin-1↗
Leukocyte-mediated endothelial cell injury and death in the diabetic retina.
Endothelial cell death is a hallmark of diabetic retinopathy. Its occurrence is required for the formation of acellular (devitalized) capillaries, lesions that produce irreversible retinal ischemia through their inability to support blood flow. The mechanisms underlying diabetic retinal endothelial cell injury and death remain largely unknown. The current study demonstrates that adherent leukocytes are temporally and spatially associated with retinal endothelial cell injury and death within 1 week of streptozotocin-induced experimental diabetes in rats. Moreover, the antibody-based neutralization of intercellular adhesion molecule-1 and CD18 is shown to prevent both leukocyte adhesion and retinal endothelial cell injury and death. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-intercellular adhesion molecule1- and anti-CD18-based therapies in the treatment of diabetic retinopathy, a newly recognized inflammatory disease.
Animals↗
Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium.
Choroidal neovascularization in age-related macular degeneration is a frequent and poorly treatable cause of vision loss in elderly Caucasians. This choroidal neovascularization has been associated with the expression of vascular endothelial growth factor (VEGF). In current animal models choroidal neovascularization is induced by subretinal injection of growth factors or vectors encoding growth factors such as VEGF, or by disruption of the Bruch's membrane/retinal pigment epithelium complex with laser treatment. We wished to establish a transgenic murine model of age-related macular degeneration, in which the overexpression of VEGF by the retinal pigment epithelium induces choroidal neovascularization. A construct consisting of a tissue-specific murine retinal pigment epithelium promoter (RPE(65) promoter) coupled to murine VEGF(164) cDNA with a rabbit beta-globin-3' UTR was introduced into the genome of albino mice. Transgene mRNA was expressed in the retinal pigment epithelium at all ages peaking at 4 months. The expression of VEGF protein was increased in both the retinal pigment epithelium and choroid. An increase of intravascular adherent leukocytes and vessel leakage was observed. Histopathology revealed intrachoroidal neovascularization that did not penetrate through an intact Bruch's membrane. These results support the hypothesis that additional insults to the integrity of Bruch's membrane are required to induce growth of choroidal vessels into the subretinal space as seen in age-related macular degeneration. This model may be useful to screen for inhibitors of choroidal vessel growth.
Age Factors↗
Solitary peripapillary hemangioblastoma. A histopathological case report.
PURPOSE: Hemangioblastomas are highly vascularized tumors of not well-defined histological origin. They are the most frequent manifestation of the von-Hippel-Lindau (VHL) disease, but also occur as sporadic non-hereditary tumors. Much has been learned in the recent past about the genetic background, however, the cellular origin of the tumor is still not resolved. METHODS: We report a rare case of sporadic peripapillary hemangioblastoma in a 58-year-old patient. RESULTS: Histological examination demonstrated a highly vascularized tumor with intercapillary stromal cells. The tumor did not invade the adjacent tissues. Surrounding retinal areas showed cystic and gliotic changes. Immunohistochemistry was unable to prove neuroglial origin of the stromal cells. CONCLUSION: Histological findings show similarities to the findings in cerebral hemangioblastomas. The tumor location in this case together with the known response of glial cells to VHL, might indicate their involvement in the pathogenesis of hemangioblastoma.
Eye Enucleation↗
Rapid ocular angiogenic control via naked DNA delivery to cornea.
PURPOSE: To determine the efficacy and safety of naked plasmid gene therapy to the corneal stroma and epithelium. METHODS: Naked plasmid DNA was injected under pressure into the cornea of mice. The expression of genes coding for beta galactosidase (beta-gal), enhanced green fluorescent protein (EGFP), vascular endothelial growth factor (VEGF), and soluble Flt-1 (s-Flt) was recorded and measured with regard to dose, time course, and bioactivity. RESULTS: LacZ gene expression of the protein beta-gal was demonstrated as early as 1 hour, with expression persisting for 10 days. Plasmid-injected corneas remained clear and free of inflammation. EGFP was bicistronically expressed with VEGF to demonstrate the practicality of simultaneous in vivo analysis of gene expression and growth factor bioactivity. Corneal injection of a plasmid containing VEGF cDNA induced corneal and anterior chamber neovascularization. Moreover, corneal injection of plasmid containing the cDNA for the soluble form of the VEGF receptor Flt-1 effectively prevented corneal neovascularization. CONCLUSIONS: The cornea is readily accessible for gene therapy in the laboratory and in the clinic. The method described is safe, effective, titratable, and easily monitored. Naked DNA delivery to the cornea has the potential to alter the treatment of a wide variety of corneal and anterior segment diseases.
Animals↗
VEGF-initiated blood-retinal barrier breakdown in early diabetes.
PURPOSE: The objectives of this study were to (1) determine whether endogenous vascular endothelial growth factor (VEGF) triggers diabetic blood-retinal barrier breakdown, and (2) identify the site as well as phenotype of the hyperpermeable diabetic retinal vessels. METHODS: Retinal VEGF mRNA levels were quantified in 1-week diabetic rats using the RNase protection assay. VEGF bioactivity was blocked via the systemic administration of a highly specific VEGF-neutralizing soluble Flt/F(c) construct (VEGF TrapA(40)). An inactive IL6 receptor/F(c) construct (IL6R Trap) was used as an isotype control. Blood-retinal barrier breakdown was quantified using the Evans blue technique and was spatially localized with fluorescent microspheres. RESULTS: Retinal VEGF mRNA levels in 1-week diabetic animals were 3.2-fold higher than in nondiabetic controls (P < 0.0001). Similarly, retinal vascular permeability in 8-day diabetic animals was 1.8-fold higher than in normal nondiabetic controls (P < 0.05). Diabetes-induced blood-retinal barrier breakdown was dose-dependently inhibited with VEGF TrapA(40), with 25 mg/kg producing complete inhibition of the diabetes-induced increases (P < 0.05). Blood-retinal barrier breakdown in diabetic animals treated with solvent alone or IL6R Trap did not differ significantly from untreated diabetic animals (P > 0.05). Spatially, early blood-retinal barrier breakdown was localized to the retinal venules and capillaries of the superficial retinal vasculature. CONCLUSIONS: Early blood-retinal barrier breakdown in experimental diabetes is VEGF dependent and is restricted, in part, to the venules and capillaries of the superficial inner retinal vasculature. VEGF inhibition should prove a useful therapeutic approach in the treatment of early diabetic blood-retinal barrier breakdown.
Animals↗