Home LiteratureArticle Details
PMID: 16123222 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Inhibition of pathologic retinal neovascularization by alpha-defensins.

Blood ·Vol. 106 ·No. 12 ·2005-12-01 ·Pages 3831-8

Economopoulou M, Bdeir K, Cines DB, Fogt F, Bdeir Y, Lubkowski J, Lu W, Preissner KT, Hammes HP, Chavakis T

Abstract

Proliferative retinopathies, such as those complicating prematurity and diabetes, are major causes of blindness. A prominent feature of these retinopathies is excessive neovascularization, which is orchestrated by the hypoxia-induced vascular endothelial growth factor (VEGF) stimulating endothelial cells and the integrin-mediated adhesive interactions of endothelial cells with extracellular matrix components such as fibronectin (FN). Recently, we demonstrated that alpha-defensins interfere with alpha5beta1-FN interactions and dependent endothelial cell functions. Here, alpha-defensins were studied in hypoxia-induced proliferative retinopathy. In vitro, alpha-defensins specifically inhibited alpha5beta1-integrin-dependent migration of bovine retinal endothelial cells (BRECs) to FN, attenuated the VEGF-stimulated increase in endothelial permeability, and blocked BREC proliferation and capillary sprout formation in 3-dimensional fibrin-matrices. An up-regulation of beta1-integrin and FN was observed in the retinal vessels in the mouse model of hypoxia-induced retinal angiogenesis. Systemic and local administration of alpha-defensins reduced retinal neovascularization by 45% and 60%, respectively, and this effect was comparable to the inhibitory effect of alpha5beta1-blocking antibody. alpha-Defensins were detected in human diabetic retinas associated with normal retinal vessels but were absent from proliferative lesions. Together, these data show that alpha-defensins inhibit pathologic retinal neovascularization in vivo and may provide a clinically efficient strategy against proliferative retinopathies.

MeSH Terms
Animals Apoptosis/drug effects,physiology Cell Adhesion/drug effects,physiology Cell Movement/drug effects,physiology Cell Proliferation/drug effects Cells, Cultured Disease Models, Animal Endothelial Cells/drug effects,metabolism Humans Hypoxia/physiopathology Immunohistochemistry In Situ Nick-End Labeling Mice Retina/metabolism,pathology,physiopathology Retinal Diseases/metabolism,physiopathology Retinal Neovascularization/metabolism,physiopathology Retinal Vessels/metabolism alpha-Defensins/metabolism,pharmacology
Chemicals
alpha-Defensins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Economopoulou Matina
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rm 4B17, 10 Center Dr, Bethesda, MD 20892, USA.
Bdeir Khalil
Cines Douglas B
Fogt Franz
Bdeir Yasmina
Lubkowski Jacek
Lu Wuyuan
Preissner Klaus T
Hammes Hans-Peter
Chavakis Triantafyllos
References (48)
48 references, click to expand
  1. Generation of biologically active angiostatin kringle 1-3 by activated human neutrophils.
    J Immunol. 2002 Jun 1;168(11):5798-804 PMID: 12023382
  2. Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration.
    Retina. 2002 Apr;22(2):143-52 PMID: 11927845
  3. A reevaluation of integrins as regulators of angiogenesis.
    Nat Med. 2002 Sep;8(9):918-21 PMID: 12205444
  4. Fibronectin fragments promote human retinal endothelial cell adhesion and proliferation and ERK activation through alpha5beta1 integrin and PI 3-kinase.
    Invest Ophthalmol Vis Sci. 2003 Apr;44(4):1704-15 PMID: 12657612
  5. VEGF-induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor.
    FASEB J. 2003 Apr;17(6):752-4 PMID: 12594181
  6. Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease.
    Nat Med. 2003 Jun;9(6):781-8 PMID: 12730690
  7. From pro defensins to defensins: synthesis and characterization of human neutrophil pro alpha-defensin-1 and its mature domain.
    J Pept Res. 2003 Aug;62(2):53-62 PMID: 12823617
  8. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization.
    J Exp Med. 2003 Aug 4;198(3):483-9 PMID: 12900522
  9. Ocular neovascularization: a valuable model system.
    Oncogene. 2003 Sep 29;22(42):6537-48 PMID: 14528278
  10. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment.
    J Exp Med. 2003 Nov 17;198(10):1507-15 PMID: 14623906
  11. The functional role of blood platelet components in angiogenesis.
    Thromb Haemost. 2004 Aug;92(2):394-402 PMID: 15269837
  12. Regulation of neovascularization by human neutrophil peptides (alpha-defensins): a link between inflammation and angiogenesis.
    FASEB J. 2004 Aug;18(11):1306-8 PMID: 15208269
  13. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A.
    Nat Med. 2004 Sep;10(9):950-8 PMID: 15334073
  14. Defensins. Natural peptide antibiotics of human neutrophils.
    J Clin Invest. 1985 Oct;76(4):1427-35 PMID: 2997278
  15. Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis.
    J Lab Clin Med. 1993 Aug;122(2):202-7 PMID: 8340706
  16. Integrin overexpression induced by high glucose and by human diabetes: potential pathway to cell dysfunction in diabetic microangiopathy.
    Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9640-4 PMID: 8415754
  17. Oxygen-induced retinopathy in the mouse.
    Invest Ophthalmol Vis Sci. 1994 Jan;35(1):101-11 PMID: 7507904
  18. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin.
    Development. 1993 Dec;119(4):1079-91 PMID: 8306876
  19. Embryonic mesodermal defects in alpha 5 integrin-deficient mice.
    Development. 1993 Dec;119(4):1093-105 PMID: 7508365
  20. Defensins: a family of antimicrobial and cytotoxic peptides.
    Toxicology. 1994 Feb 28;87(1-3):131-49 PMID: 7512758
  21. Neutrophil defensins: purification, characterization, and antimicrobial testing.
    Methods Enzymol. 1994;236:160-72 PMID: 7968608
  22. Fibronectin, laminin, vitronectin and their receptors at newly-formed capillaries in proliferative diabetic retinopathy.
    Exp Eye Res. 1995 Jan;60(1):5-17 PMID: 7536680
  23. Beta 1- and beta 3-class integrins mediate fibronectin binding activity at the surface of developing mouse peri-implantation blastocysts. Regulation by ligand-induced mobilization of stored receptor.
    J Biol Chem. 1995 May 12;270(19):11522-31 PMID: 7538116
  24. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins.
    Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10457-61 PMID: 7479819
  25. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.
    Nat Med. 1995 Oct;1(10):1024-8 PMID: 7489357
  26. Fibronectin overexpression in retinal microvessels of patients with diabetes.
    Invest Ophthalmol Vis Sci. 1996 Feb;37(2):258-66 PMID: 8603829
  27. Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity.
    Invest Ophthalmol Vis Sci. 1996 Feb;37(2):290-9 PMID: 8603833
  28. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization.
    Nat Med. 1996 May;2(5):529-33 PMID: 8616710
  29. Defensin modulates tissue-type plasminogen activator and plasminogen binding to fibrin and endothelial cells.
    J Biol Chem. 1996 Jul 26;271(30):17650-5 PMID: 8663495
  30. Immunohistochemical localization of defensin in human coronary vessels.
    Am J Pathol. 1997 Mar;150(3):1009-20 PMID: 9060838
  31. Purification and characterization of defensins from cystic fibrosis sputum.
    Inflamm Res. 1997 Mar;46(3):98-102 PMID: 9098722
  32. Defensin stimulates the binding of lipoprotein (a) to human vascular endothelial and smooth muscle cells.
    Blood. 1997 Jun 15;89(12):4290-8 PMID: 9192751
  33. Angiopoietin-1 induces sprouting angiogenesis in vitro.
    Curr Biol. 1998 Apr 23;8(9):529-32 PMID: 9560344
  34. Combretastatin A-4 prodrug in the treatment of a murine model of retinoblastoma.
    Invest Ophthalmol Vis Sci. 2005 Jan;46(1):8-11 PMID: 15623747
  35. Endostatin modulates VEGF-mediated barrier dysfunction in the retinal microvascular endothelium.
    Exp Eye Res. 2005 Jul;81(1):22-31 PMID: 15978251
  36. Integrin signaling.
    Science. 1999 Aug 13;285(5430):1028-32 PMID: 10446041
  37. Defensin promotes the binding of lipoprotein(a) to vascular matrix.
    Blood. 1999 Sep 15;94(6):2007-19 PMID: 10477730
  38. Effects of intraocular or systemic administration of neutralizing antibody against vascular endothelial growth factor on the murine experimental model of retinopathy.
    Life Sci. 1999;65(24):2573-80 PMID: 10619365
  39. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin.
    Am J Pathol. 2000 Apr;156(4):1345-62 PMID: 10751360
  40. Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1).
    Am J Pathol. 2000 May;156(5):1733-9 PMID: 10793084
  41. Immunohistochemical staining of human alpha-defensin-1 (HNP-1), in the submandibular glands of patients with oral carcinomas.
    Anticancer Res. 2000 Mar-Apr;20(2B):1125-7 PMID: 10810407
  42. Different mechanisms define the antiadhesive function of high molecular weight kininogen in integrin- and urokinase receptor-dependent interactions.
    Blood. 2000 Jul 15;96(2):514-22 PMID: 10887113
  43. The structure of human beta-defensin-2 shows evidence of higher order oligomerization.
    J Biol Chem. 2000 Oct 20;275(42):32911-8 PMID: 10906336
  44. Leukocyte-mediated endothelial cell injury and death in the diabetic retina.
    Am J Pathol. 2001 Jan;158(1):147-52 PMID: 11141487
  45. Neutrophil defensins mediate acute inflammatory response and lung dysfunction in dose-related fashion.
    Am J Physiol Lung Cell Mol Physiol. 2001 May;280(5):L947-54 PMID: 11290519
  46. Adhesion events in angiogenesis.
    Curr Opin Cell Biol. 2001 Oct;13(5):563-8 PMID: 11544024
  47. Antimicrobial polypeptides in host defense of the respiratory tract.
    J Clin Invest. 2002 Mar;109(6):693-7 PMID: 11901174
  48. Intraocular distribution of 70-kDa dextran after subconjunctival injection in mice.
    Invest Ophthalmol Vis Sci. 2002 Jun;43(6):1809-16 PMID: 12036983
Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2005-03-0889
Published
2005-12-01
Epub
2005-00-25
Pages
3831-8
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895098
Subset
IM
Grants
NHLBI NIH HHS · P01 HL076406 · United States
External Links
PubMed source DOI: 10.1182/blood-2005-03-0889 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2