title: Role of alpha 4 integrin (CD49d) in the pathogenesis of diabetic retinopathy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Eirini
authors: E
authors: Iliaki
authors: Vassiliki
authors: V
authors: Poulaki
authors: Nicholas
authors: N
authors: Mitsiades
authors: Constantine S
authors: CS
authors: Mitsiades
authors: Joan W
authors: JW
authors: Miller
authors: Evangelos S
authors: ES
authors: Gragoudas
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking; D001813:Blood-Retinal Barrier; D002199:Capillary Permeability; D002448:Cell Adhesion; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000209:etiology* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D039441:Integrin alpha4 / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology; D018921:Leukostasis / Q000209:etiology / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012171:Retinal Vessels / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D039441:Integrin alpha4