Role of 4 Integrin (CD49d) in the Pathogenesis of Diabetic Retinopathy

ArticleinInvestigative ophthalmology & visual science 50(10):4898-904 · July 2009with15 Reads
DOI: 10.1167/iovs.08-2013 · Source: PubMed
The pathophysiology of diabetic retinopathy is mediated by leukocyte adhesion to the vascular endothelium of the diabetic retina, which results in endothelial injury, blood-retina barrier breakdown, and capillary nonperfusion. Leukocyte adhesion is triggered by the interaction of vascular endothelium adhesion molecules, such as ICAM-1, with leukocyte integrins, such as CD18. Inhibition of ICAM-1/CD18 signaling suppresses but does not completely abolish the cardinal manifestations of diabetic retinopathy, suggesting a role for additional adhesion molecules. Integrin alpha 4 (CD49d), in complex with integrin beta1, forms very late antigen-4 (VLA-4), which interacts with vascular cell adhesion molecule-1. The authors have now studied the role of integrin alpha 4/CD49d in the pathogenesis of diabetic retinopathy. Diabetes mellitus was induced in Long Evans rats with streptozotocin, and an anti-alpha 4 integrin/CD49d neutralizing antibody was injected 5 and 10 days later. Two weeks after streptozotocin administration, vascular leakage was quantified with the Evans Blue technique. Leukostasis was measured with a static adhesion assay ex vivo and the FITC-lectin perfusion method in vivo. Retinal VEGF and TNF-alpha levels and NF-kappaB activity were measured by ELISA. Blockade of alpha 4 integrin/CD49d attenuated the diabetes-induced upregulation of NF-kappaB activation, VEGF, and TNF-alpha protein levels and reduced significantly diabetes-induced leukocyte adhesion and vascular leakage. These data identify alpha 4 integrin/CD49d as a mediator of leukocyte adhesion and the resultant early signature abnormalities of diabetic retinopathy. Inhibition of this signaling pathway may hold promise for clinical activity in patients with diabetes.
    • "Inhibition of integrin α4 reduced expression of VEGF, as well as vascular hemorrhage in vivo (Iliaki et al. 2009). Moreover, inhibitors of various integrins including αvβ3, αvβ5 and α5β1 have been shown to inhibit retinal neovascularization in animal models of proliferative retinopathy (Riecke et al. 2001; Iliaki et al. 2009; Yoshida et al. 2012 ) and retinopathy of prematurity (Luna et al. 1996; Witmer et al. 2002; Economopoulou et al. 2005; Wilkinson-Berka et al. 2006). Other factors thought to play a role in retinal neovascularization include stromal-derived growth factor 1 and its receptor CXCR4 (Lima e Silva et al. 2007), platelet-derived growth factor B, placental growth factor and pigment epithelium-derived factor (Seo et al. 2000; Luttun et al. 2002; Mori et al. 2002; Ogata et al. 2002 Ogata et al. , 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Ocular neovascularization can affect almost all the tissues of the eye: the cornea, the iris, the retina, and the choroid. Pathological neovascularization is the underlying cause of vision loss in common ocular conditions such as diabetic retinopathy, retinopathy of prematurity and age-related macular neovascularization. Glycosylation is the most common covalent posttranslational modification of proteins in mammalian cells. A growing body of evidence demonstrates that glycosylation influences the process of angiogenesis and impacts activation, proliferation, and migration of endothelial cells as well as the interaction of angiogenic endothelial cells with other cell types necessary to form blood vessels. Recent studies have provided evidence that members of the galectin class of β-galactoside-binding proteins modulate angiogenesis by novel carbohydrate-based recognition systems involving interactions between glycans of angiogenic cell surface receptors and galectins. This review discusses the significance of glycosylation and the role of galectins in the pathogenesis of ocular neovascularization.
    Article · Aug 2014
    • "Integrins are also among various factors that cause retinal detachment in proliferative diabetic retinopathy and proliferative vitreoretinopathy (Kupper and Ferguson 1993; Guidry et al. 2003). In rats, blockade of α4 integrin diminished diabetes-induced increase in NF-kappaB activation , VEGF and TNF-alpha levels and significantly reduced leukocyte adhesion and vascular leakage (Iliaki et al. 2009). Synthetic peptide antagonists of integrin αvβ3 inhibited retinal neovascularization in a murine model when administered as intraperitonal or periocular injections (Luna et al. 1996), inhibition of αv integrins prevented basic fibroblast growth factor-induced neovascularization of cornea (Klotz et al. 2000), and inhibition of α5β1 inhibited and regressed corneal neovascularization after alkali-burns (Muether et al. 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Several studies have established the role of activated corneal keratocytes in the fibrosis of the cornea. However, the role of keratocytes in maintaining the structural integrity of a normal cornea is less appreciated. We focus on the probable functions of integrins in the eye and of the importance of integrin-mediated keratocyte interactions with stromal matrix in the maintenance of corneal integrity. We point out that further understanding of how keratocytes interact with their matrix could establish a novel direction in preventing corneal pathology including loss of structural integrity as in keratoconus or as in fibrosis of the corneal stroma.
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    • "Previously, CD29/integrin β1 [52], CD51/integrin αV, and CD44/HCAM have been described to be present on the surface of hRPE cells [45, 53, 54], but we detected more positivity for integrin α1 and integrin α2 in our primary hRPE cell cultures compared to the studies published to date [53]. Our fvERM cells expressed low levels of the α-subunit-containing integrins, besides a reported expression of integrin α4 in diabetic retinopathy [53, 55]. Interestingly, the presence of integrin β2 subunit has been considered important factor in the RPE-T cell interaction [56]. "
    [Show abstract] [Hide abstract] ABSTRACT: Characterization of the cell surface marker phenotype of ex vivo cultured cells growing out of human fibrovascular epiretinal membranes (fvERMs) from proliferative diabetic retinopathy (PDR) can give insight into their function in immunity, angiogenesis, and retinal detachment. FvERMs from uneventful vitrectomies due to PDR were cultured adherently ex vivo. Surface marker analysis, release of immunity- and angiogenesis-pathway-related factors upon TNF α activation and measurement of the intracellular calcium dynamics upon mechano-stimulation using fluorescent dye Fura-2 were all performed. FvERMs formed proliferating cell monolayers when cultured ex vivo, which were negative for endothelial cell markers (CD31, VEGFR2), partially positive for hematopoietic- (CD34, CD47) and mesenchymal stem cell markers (CD73, CD90/Thy-1, and PDGFR β ), and negative for CD105. CD146/MCAM and CD166/ALCAM, previously unreported in cells from fvERMs, were also expressed. Secretion of 11 angiogenesis-related factors (DPPIV/CD26, EG-VEGF/PK1, ET-1, IGFBP-2 and 3, IL-8/CXCL8, MCP-1/CCL2, MMP-9, PTX3/TSG-14, Serpin E1/PAI-1, Serpin F1/PEDF, TIMP-1, and TSP-1) were detected upon TNF α activation of fvERM cells. Mechano-stimulation of these cells induced intracellular calcium propagation representing functional viability and role of these cells in tractional retinal detachment, thus serving as a model for studying tractional forces present in fvERMs in PDR ex vivo.
    Full-text · Article · Aug 2013
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