title: Ang-2 upregulation correlates with increased levels of MMP-9, VEGF, EPO and TGFβ1 in diabetic eyes undergoing vitrectomy.
abstract: OBJECTIVE
  Angiogenesis in diabetic retinopathy (DR) is a multifactorial process regulated by hypoxia-induced growth factors and inflammatory cytokines. In addition to the angiogenic switch, the proteolytic processing and altered synthesis of the extracellular matrix are critical steps in this disease. This study was performed to evaluate the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9), angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), vascular endothelial growth factor (VEGF), erythropoietin (EPO) and transforming growth factor-β1 (totalTGFβ1) in the vitreous of diabetic eyes undergoing vitrectomy compared with control eyes operated because of macular hole or pucker.
  
  
  METHODS
  Prospective consecutive controlled observational study performed in the unit of vitreoretinal surgery in Finland during the years 2006-2008. Vitreous samples were collected before the start of the conventional 3-ppp vitrectomy. Vitreous MMP-2 and MMP-9, Ang-1 and Ang-2, VEGF, EPO and TGFβ1 concentrations were measured from 69 patients with Type 1 or 2 diabetes and 40 controls.
  
  
  RESULTS
  Comparison of eyes with DR with controls revealed that the mean vitreous concentrations of proMMP-2 (p = 0.0015), totalMMP-2 (p = 0.0011), proMMP-9 (p = 0.00001), totalMMP-9 (p < 0.00001), Ang-2 (p < 0.00001), VEGF (p < 0.00001), EPO (p < 0.00001) and totalTGFβ1 (p = 0.000026) were significantly higher in the former group. A multivariate logistic regression analysis suggested intravitreal Ang-2 concentration being the key marker of PDR (p = 0.00025) (OR = 1507.9).
  
  
  CONCLUSIONS
  The main new finding is that the intravitreal concentrations of Ang-2 correlated significantly with MMP-9, VEGF, EPO and TGFβ1 levels in diabetic eyes undergoing vitrectomy. Thus, these factors could promote retinal angiogenesis synergistically.
authors.affiliation: Unit of Vitreoretinal Surgery, Department of Ophthalmology, Helsinki University Central Hospital, Finland. sirpa.loukovaara@hus.fi
authors.forename: Sirpa
authors.initials: S
authors.lastname: Loukovaara
authors.forename: Alexandra
authors.initials: A
authors.lastname: Robciuc
authors.forename: Juha M
authors.initials: JM
authors.lastname: Holopainen
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehti
authors.forename: Timo
authors.initials: T
authors.lastname: Pessi
authors.forename: Johanna
authors.initials: J
authors.lastname: Liinamaa
authors.forename: Kirsi-Tiina
authors.initials: KT
authors.lastname: Kukkonen
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
authors.forename: Jorma
authors.initials: J
authors.lastname: Keski-Oja
authors.forename: Ilkka
authors.initials: I
authors.lastname: Immonen
mesh_terms: D000368:Aged; D042683:Angiopoietin-1 / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000601:surgery; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D011446:Prospective Studies; D015861:Retinal Neovascularization / Q000378:metabolism; D012167:Retinal Perforations / Q000378:metabolism; D041623:Tomography, Optical Coherence; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D014821:Vitrectomy; D014822:Vitreous Body / Q000378:metabolism
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; C554270:EPO protein, human; D053773:Transforming Growth Factor beta1; C467484:VEGFA protein, human; C555023:VPS51 protein, human; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; D004921:Erythropoietin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: angiogenesis; angiopoietin-1; angiopoietin-2; diabetic retinopathy; erythropoietin; matrix metalloproteinases; proliferative diabetic retinopathy; proliferative diabetic vitreoretinopathy; traction retinal detachment; transforming growth factor-β1; vascular endothelial growth factor; vitrectomy