Download PDF
Horm Metab Res 2003; 35(6): 382-386
DOI: 10.1055/s-2003-41362
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

Proliferative Diabetic Retinopathy is Associated with a Low Level of the Natural Ocular Anti-angiogenic Agent Pigment Epithelium-derived Factor (PEDF) in Aqueous Humor. A Pilot Study

B.  O.  Boehm 1 , G.  Lang 2 , B.  Feldmann 1 , A.  Kurkhaus 1 , S.  Rosinger 1 , O.  Volpert 3, 4 , G.  K.  Lang 2 , N.  Bouck 4, 5
  • 1 Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Ulm Medical School, Ulm, Germany
  • 2 Department of Ophthalmology, University of Ulm Medical School, Ulm, Germany
  • 3 Department of Urology, Northwestern University Medical School, Chicago, IL, USA
  • 4 The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, IL, USA
  • 5 Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL, USA
Further Information

Publication History

Received 14 August 2002

Accepted after second Revision 30 December 2002

Publication Date:
15 August 2003 (online)

Also available at
    Permissions and Reprints

Abstract

Retinopathy is the most common microvascular diabetes complication and represents a major threat to the eyesight. The aim of this study was to address the role of pro- and anti-angiogenic molecules in diabetic retinopathy in the aqueous humor of the eye. Aqueous humor was collected at cataract surgery from 19 diabetic patients and from 13 age- and sex-matched normoglycemic controls. Levels of pro-angiogenic vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) were determined. Angiogenic activity of the aqueous humor was quantified by measuring its effect on the migration of capillary endothelial cells.

In the aqueous fluid, VEGF levels were increased in diabetics (mean values: 501 vs. 367 pg/ml; p = 0.05), compared to controls. PEDF was found to be decreased in diabetics (mean values: 2080 vs. 5780 ng/ml; p = 0.04) compared to controls. In seven diabetic patients with proliferative retinopathy, the most profound finding was a significant decrease of the PEDF level (mean value: 237 ng/ml), whereas VEGF levels were comparable to diabetic patients without proliferation (mean value: 3153; p = 0.003). Angiogenic activity in samples of patients from the control group was generally inhibitory due to PEDF, and inhibition was blocked by neutralizing antibodies to PEDF. Likewise, in diabetics without proliferation, angiogenic activity was also blocked by antibodies to PEDF.

We will demonstrate here that the level of the natural ocular anti-angiogenic agent PEDF is inversely associated with proliferative retinopathy. PEDF is an important negative regulator of angiogenic activity of aqueous humor. Our data may have implications for the development of novel regimens for diabetic retinopathy.

Key words

Angiogenesis - Angiogenic Inhibitors - Aqueous Humor - Diabetic Retinopathy - Pigment Epithelium-Derived Factor (PEDF) - Vascular Endothelial Growth Factor (VEGF)

References

  • 1 Klein R. The epidemiology of eye disease. In: Pickup JC, Williams G (eds) Textbook of Diabetes, 2nd edition. Oxford; Blackwell Sciences 1997: 44.1-44.9
    Google Scholar
  • 2 The Diabetes Control and Complications Trial Research Group . The effects of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.  N Engl J Med. 1993;  329 977-986
    Google Scholar
  • 3 The Diabetes Control and Complications Trial Research Group . Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group.  N Engl J Med. 2000;  342 381-389
    CrossrefPubMedGoogle Scholar
  • 4 UK Prospective Diabetes Study (UKPDS) Group . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet. 1998;  352 837-853
    CrossrefPubMedGoogle Scholar
  • 5 Klein R, Klein B EK, Moss S E, Cruickshanks K J. The Wisconsin Epidemiologic study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy.  Arch Ophthalmol. 1994;  112 1217-1228
    PubMedGoogle Scholar
  • 6 Bouck N, Stellmach V, Hsu S. How tumors become angiogenic.  Adv Cancer Res. 1996;  69 135-174
    PubMedGoogle Scholar
  • 7 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.  Cell. 1996;  86 353-364
    CrossrefPubMedGoogle Scholar
  • 8 Bouck N. PEDF: anti-angiogenic guardian of ocular function.  Trends Mol Med. 2002;  8 330-334
    CrossrefPubMedGoogle Scholar
  • 9 Feldmann B, Jehle P M, Mohan S, Lang G E, Lang G K, Brueckel J, Boehm B O. Diabetic retinopathy is associated with decreased serum levels of free IGF-I and changes of IGF-binding proteins.  Growth Horm and IGF Res. 2000;  10 53-60
    PubMedGoogle Scholar
  • 10 Poulaki V, Qin W, Joussen A M, Hurlbut P, Wiegand S J, Rudge J, Yancopoulos G D, Adamis A P. Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1α and VEGF.  J Clin Invest. 2002;  109 805-815
    CrossrefPubMedGoogle Scholar
  • 11 Adamis A P, Miller J W, Bdernal M-T, D'Amico D J, Folkman J, Yeo T-K, Yeo K-T. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy.  Am J Ophthalmol. 1994;  118 445-450
    CrossrefPubMedGoogle Scholar
  • 12 Aiello L P, Avery R L, Arrigg P G. et al . Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.  N Engl J Med. 1994;  331 1480-1487
    CrossrefPubMedGoogle Scholar
  • 13 Aiello L P, Pierce E A, Foley E D, Takagi H, Chen H, Riddle L, Ferrara N, King G L, Smith L E. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins.  Proc Natl Acad Sci USA. 1995;  92 10 457-10 461
    PubMedGoogle Scholar
  • 14 Dawson D W, Volpert O V, Gillis P, Crawford S E, Xu H, Benedict W, Bouck N P. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis.  Science. 1999;  285 245-248
    CrossrefPubMedGoogle Scholar
  • 15 Brausewetter F, Jehle P M, Jung M F, Boehm B O, Brueckel J, Hombach V, Osterhues H H. Microvascular permeability is increased in both types of diabetes and correlates differentially with serum levels of insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF).  Horm Metab Res. 2001;  33 713-720
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Miller A D, Robinson G S, Smith L EH, Becerra S P. Regulation of pigment epithelium-derived factor (PEDF) production by oxygen.  Invest Ophthalmol Vis Sci. 2000;  41 (Suppl) S869-S874
    PubMedGoogle Scholar
  • 17 Gao G, Li Y, Zhang D, Gee S, Crosson G, Ma J. Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization.  FEBS Lett. 2001;  489 270-276
    CrossrefPubMedGoogle Scholar
  • 18 Okamoto T, Oikawa S, Toyota T. Absence of angiogenesis-inhibitory activity in aqueous humor of diabetic rabbits.  Diabetes. 1990;  39 12-16
    PubMedGoogle Scholar
  • 19 Tapper D, Langer R, Bellows A R, Folkman J. Angiogenesis capacity as a diagnostic marker for human eye tumors.  Surgery. 1979;  86 36-40
    PubMedGoogle Scholar
  • 20 Ortego J, Escribano J, Beccera S P, Coca-Prados M. Gene expression of the neurotrophic pigment epithelium-derived factor in the human ciliary epithelium: synthesis and secretion into the aqueous humor.  Invest Ophthalmol Vis Sci. 1996;  37 2759-2767
    PubMedGoogle Scholar
  • 21 Ogata N, Wada M, Otsuji T, Jo N, Tombran-Tink J, Matsumura M. Expression of pigment epithelium-derived factor in normal adult rat eye and experimental choroidal neovascularization.  Invest Ophthalmol Vis Sci. 2002;  43 1168-1175
    PubMedGoogle Scholar
  • 22 Stellmach V, Crawford S E, Zhou W, Bouck N. Prevention of ischemia induced retinopathy by the natural ocular anti-angiogenic agent pigment epithelium-derived factor.  Proc Natl Acad Sci USA. 2001;  98 2593-2597
    CrossrefPubMedGoogle Scholar
  • 23 Chader G J. PEDF: raising both hopes and questions in controlling angiogenesis.  Proc Natl Acad Sci USA. 2001;  98 2122-2124
    CrossrefPubMedGoogle Scholar
  • 24 Becerra S P. Structure-function studies on PEDF a noninhibitory serpin with neurotrophic activity.  Adv Exp Med Biol. 1997;  425 223-237
    PubMedGoogle Scholar
  • 25 Mori K, Gehlbach P, Ando A, McVey D, Wei L, Campochiaro P A. Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor.  Invest Ophthalmol Vis Sci. 2002;  43 2428-2434
    PubMedGoogle Scholar
  • 26 Cayouette M, Smith S B, Becerra S P, Gravel C. Pigment epithelium-derived factor delays the death of photoreceptors in mouse models of inherited retinal degenerations.  Neurobiol Dis. 1999;  6 523-532
    CrossrefPubMedGoogle Scholar
  • 27 Bilak M M, Corse A M, Bilak S R, Lehar M, Tombran-Tink J, Kuncl R W. Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration.  J Neuropathol Exp Neurol. 1999;  58 719-728
    PubMedGoogle Scholar
  • 28 Cao W, Tombran-Tink J, Elias R, Sezate S, Mrazek D, McGinns J F. In vivo protection of photoreceptors from light damage by pigment epithelium-derived factor.  Investigative Ophthalmol Vis Sci. 2001;  42 1646-1652
    PubMedGoogle Scholar
  • 29 Ohno-Matsui K, Morita I, Tombran-Tink J, Mrazek D, Onodera M, Uetama T, Hayano M, Murota S-I, Mochizuki M. Novel mechanisms for age-related macular degeneration: An equilibrium shift between the angiogenesis factors VEGF and PEDF.  J Cell Physiol. 2001;  189 323-333
    CrossrefPubMedGoogle Scholar
  • 30 Holekamp N M, Bouck N, Volpert O. Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration.  Am J Ophthalmol. 2002;  134 220-227
    CrossrefPubMedGoogle Scholar
  • 31 Spranger J, Osterhoff M, Reimann M, Möhlig M, Ristow M, Francis M F, Cristofalo V, Hames H-P, Smith G, Boulton M, Pfeiffer A FH. Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease.  Diabetes. 2001;  50 2641-2645
    PubMedGoogle Scholar
  • 32 Boehm B O, Lang G K, Jehle P M, Feldmann B*, Lang G E*. Octreotide reduces risk for vitreous hemorrhages and loss of visual acuity in patients with high risk proliferative diabetic retinopathy.  Horm Metab Res. 2001;  33 300-306 (* contributed equally)
    Article in Thieme ConnectPubMedGoogle Scholar

Prof. Bernhard O. Boehm, M. D.

Division of Endocrinology and Diabetes, University of Ulm ·

Robert-Koch-Strasse 8, 89081 Ulm, Germany

Phone: + 49 (731) 500-24304

Fax: + 49 (731) 500-23938 ·

Email: bernhard.boehm@medizin.uni-ulm.de

      >