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1.
PLoS One ; 9(9): e106507, 2014.
Article in English | MEDLINE | ID: mdl-25188381

ABSTRACT

BACKGROUND: Vision loss due to vascular disease of the retina is a leading cause of blindness in the world. Retinal angiomatous proliferation (RAP) is a subgroup of neovascular age-related macular degeneration (AMD), whereby abnormal blood vessels develop in the retina leading to debilitating vision loss and eventual blindness. The novel mouse strain, neoretinal vascularization 2 (NRV2), shows spontaneous fundus changes associated with abnormal neovascularization. The purpose of this study is to characterize the induction of pathologic angiogenesis in this mouse model. METHODS: The NRV2 mice were examined from postnatal day 12 (p12) to 3 months. The phenotypic changes within the retina were evaluated by fundus photography, fluorescein angiography, optical coherence tomography, and immunohistochemical and electron microscopic analysis. The pathological neovascularization was imaged by confocal microscopy and reconstructed using three-dimensional image analysis software. RESULTS: We found that NRV2 mice develop multifocal retinal depigmentation in the posterior fundus. Depigmented lesions developed vascular leakage observed by fluorescein angiography. The spontaneous angiogenesis arose from the retinal vascular plexus at postnatal day (p)15 and extended toward retinal pigment epithelium (RPE). By three months of age, histological analysis revealed encapsulation of the neovascular lesion by the RPE in the photoreceptor cell layer and subretinal space. CONCLUSIONS: The NRV2 mouse strain develops early neovascular lesions within the retina, which grow downward towards the RPE beginning at p15. This retinal neovascularization model mimics early stages of human retinal angiomatous proliferation (RAP) and will likely be a useful in elucidating targeted therapeutics for patients with ocular neovascular disease.


Subject(s)
Retinal Neovascularization/pathology , Animals , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Fluorescein Angiography , Longitudinal Studies , Mice , Pigment Epithelium of Eye/pathology , Retina/pathology , Tomography, Optical Coherence
2.
Proc Natl Acad Sci U S A ; 111(26): 9603-8, 2014 Jul 01.
Article in English | MEDLINE | ID: mdl-24979774

ABSTRACT

Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)-epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD.


Subject(s)
Choroidal Neovascularization/drug therapy , Cytochrome P-450 Enzyme System/metabolism , Fatty Acids, Omega-3/pharmacology , Food, Fortified , Macular Degeneration/physiopathology , Animals , Arachidonic Acids , Chromatography, Liquid , DNA, Complementary/genetics , Enzyme-Linked Immunosorbent Assay , Fatty Acids, Omega-3/therapeutic use , Flow Cytometry , Immunoblotting , Laser Capture Microdissection , Macular Degeneration/drug therapy , Mice , PPAR gamma/metabolism , Real-Time Polymerase Chain Reaction , Tandem Mass Spectrometry
3.
Am J Pathol ; 182(1): 255-65, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23141926

ABSTRACT

Neovascular diseases of the eye are the most common causes of blindness worldwide. The mechanisms underlying pathological neovascularization in the retina remain incompletely understood. PGC-1α is a transcriptional coactivator that plays a central role in the regulation of cellular metabolism. In skeletal muscle, PGC-1α induces VEGFA expression and powerfully promotes angiogenesis, suggesting a similar role in other tissues. This study investigates the role of PGC-1α during normal and pathological vascularization in the retina. We show that PGC-1α induces the expression of VEGFA in numerous retinal cells, and that PGC-1α expression is strongly induced during postnatal retinal development, coincident with VEGFA expression and angiogenesis. PGC-1α(-/-) mice have a significant reduction of early retinal vascular outgrowth, and reduced density of capillaries and number of main arteries and veins as adults. In the oxygen-induced retinopathy model of retinopathy of prematurity, PGC-1α expression is dramatically induced in the inner nuclear layer of the retina, suggesting that PGC-1α drives pathological neovascularization. In support of this, PGC-1α(-/-) mice subjected to oxygen-induced retinopathy had decreased expression of VEGFA and were protected against pathological neovascularization. These results demonstrate that PGC-1α regulates VEGFA in the retina and is required for normal vessel development and for pathological neovascularization. The data highlight PGC-1α as a novel target in the treatment of neovascular diseases of the eye.


Subject(s)
Neovascularization, Physiologic/physiology , Retinal Neovascularization/metabolism , Retinal Vessels/metabolism , Trans-Activators/physiology , Animals , Disease Models, Animal , Gene Expression Regulation/physiology , Humans , Infant, Newborn , Mice , Mice, Knockout , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Retina/growth & development , Retina/metabolism , Retina/pathology , Retinal Neovascularization/pathology , Retinal Neovascularization/prevention & control , Retinal Vessels/growth & development , Retinal Vessels/pathology , Retinopathy of Prematurity/metabolism , Retinopathy of Prematurity/prevention & control , Trans-Activators/biosynthesis , Trans-Activators/deficiency , Transcription Factors , Vascular Endothelial Growth Factor A/biosynthesis , Vascular Endothelial Growth Factor A/genetics
4.
Arterioscler Thromb Vasc Biol ; 28(4): 665-71, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18202322

ABSTRACT

OBJECTIVE: TGF-beta plays a significant role in vascular injury-induced stenosis. This study evaluates the efficacy of a novel, small molecule inhibitor of ALK5/ALK4 kinase, in the rat carotid injury model of vascular fibrosis. METHODS AND RESULTS: The small molecule, SM16, was shown to bind with high affinity to ALK5 kinase ATP binding site using a competitive binding assay and biacore analysis. SM16 blocked TGF-beta and activin-induced Smad2/3 phosphorylation and TGF-beta-induced plasminogen activator inhibitor (PAI)-luciferase activity in cells. Good overall selectivity was demonstrated in a large panel of kinase assays, but SM16 also showed nanomolar inhibition of ALK4 and weak (micromolar) inhibition of Raf and p38. In the rat carotid injury model, SM16 dosed once daily orally at 15 or 30 mg/kg SM16 for 14 days caused significant inhibition of neointimal thickening and lumenal narrowing. SM16 also prevented induction of adventitial smooth muscle alpha-actin-positive myofibroblasts and the production of intimal collagen, but did not decrease the percentage of proliferative cells. CONCLUSIONS: These results are the first to demonstrate the efficacy of an orally active, small-molecule ALK5/ALK4 inhibitor in a vascular fibrosis model and suggest the potential therapeutic application of these inhibitors in vascular fibrosis.


Subject(s)
Azabicyclo Compounds/pharmacology , Carotid Artery Injuries/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Activin Receptors, Type I/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Administration, Oral , Animals , Azabicyclo Compounds/administration & dosage , Azabicyclo Compounds/metabolism , Binding Sites , Carotid Artery Injuries/pathology , Carotid Artery Injuries/physiopathology , Cell Line , Fibroblasts/drug effects , Fibroblasts/pathology , Fibrosis , Humans , Male , Myoblasts, Smooth Muscle/drug effects , Myoblasts, Smooth Muscle/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Transforming Growth Factor-beta Type I , Transforming Growth Factor beta/physiology
5.
Proc Natl Acad Sci U S A ; 104(36): 14430-5, 2007 Sep 04.
Article in English | MEDLINE | ID: mdl-17726113

ABSTRACT

The nervous system-specific leucine-rich repeat Ig-containing protein LINGO-1 is associated with the Nogo-66 receptor complex and is endowed with a canonical EGF receptor (EGFR)-like tyrosine phosphorylation site. Our studies indicate that LINGO-1 expression is elevated in the substantia nigra of Parkinson's disease (PD) patients compared with age-matched controls and in animal models of PD after neurotoxic lesions. LINGO-1 expression is present in midbrain dopaminergic (DA) neurons in the human and rodent brain. Therefore, the role of LINGO-1 in cell damage responses of DA neurons was examined in vitro and in experimental models of PD induced by either oxidative (6-hydroxydopamine) or mitochondrial (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity. In LINGO-1 knockout mice, DA neuron survival was increased and behavioral abnormalities were reduced compared with WT. This neuroprotection was accompanied by increased Akt phosphorylation (p-Akt). Similar neuroprotective in vivo effects on midbrain DA neurons were obtained in WT mice by blocking LINGO-1 activity using LINGO-1-Fc protein. Neuroprotection and enhanced neurite growth were also demonstrated for midbrain DA neurons in vitro. LINGO-1 antagonists (LINGO-1-Fc, dominant negative LINGO-1, and anti-LINGO-1 antibody) improved DA neuron survival in response to MPP+ in part by mechanisms that involve activation of the EGFR/Akt signaling pathway through a direct inhibition of LINGO-1's binding to EGFR. These results show that inhibitory agents of LINGO-1 activity can protect DA neurons against degeneration and indicate a role for the leucine-rich repeat protein LINGO-1 and related classes of proteins in the pathophysiological responses of midbrain DA neurons in PD.


Subject(s)
Dopamine/biosynthesis , Membrane Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neurons/cytology , Neurons/metabolism , Parkinson Disease/metabolism , Parkinson Disease/pathology , Animals , Cell Line , Cell Survival , Disease Models, Animal , Gene Expression Regulation , Humans , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Knockout , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Neurites/metabolism , Parkinson Disease/genetics
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