Abstract
Corneal neovascularization, which occurs in many pathologic states of the cornea, reduces the visual acuity. Recently, we found that the extracellular region of brain-specific angiogenesis inhibitor 1 (BAI1-ECR) has antiproliferative activity through functional blocking of αvβ5 integrin in endothelial cells. In this study, we investigated the effects of lipid-mediated subconjunctival injection of the BAI1-ECR gene on corneal angiogenesis induced by epithelial debridement by heptanol in the rabbit. When a pEGFP-BAI1-ECR plasmid was given subconjunctivally 1 week after epithelial debridement, green fluorescence was detected in the corneal stroma with expression persisting for 7 days. To test the effect of BAI1-ECR on neovascularization, rabbits were injected with the BAI1-ECR gene or empty vector two or three times at 1-week intervals beginning 1 week after debridement. When measured with biomicroscopy at 1 or 2 weeks after two weekly injections, BAI1-delivered eyes had significantly less neovascularized corneal area than vector-injected ones in both time periods. Similar microscopic results were obtained after three weekly injections of BAI1-ECR. In quantitative histological examination, the BAI1-receiving eyes showed significantly less neovascular area and number of vessels than vector-injected ones. Also, after two weekly injections, BAI1-delivered eyes had decreased neovascularized corneal area equivalent to that of anti-VEGF antibody-injected ones. These results indicate that BAI1-ECR gene delivery effectively reduces experimental corneal neovascularization and suggest that the BAI1-ECR protein can be used as an angiogenesis suppressor in the eye.
Similar content being viewed by others
References
Chang JH, Gabison EE, Kato T, Azar DT . Corneal neovascularization. Curr Opin Ophthalmol 2001; 12: 242–249.
Folkman J . Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27–31.
Duenas Z et al. Inhibition of rat corneal angiogenesis by 16-kDa prolactin and by endogenous prolactin-like molecules. Invest Ophthalmol Vis Sci 1999; 40: 2498–2505.
Auerbach W, Auerbach R . Angiogenesis inhibition: a review. Pharmacol Ther 1994; 63: 265–311.
Moses MA, Sudhalter J, Langer R . Identification of an inhibitor of neovascularization from cartilage. Science 1990; 248: 1408–1410.
Casey R, Li WW . Factors controlling ocular angiogenensis. Am J Ophthalmol 1997; 124: 521–529.
Lin HC et al. Endostatin localization in the cornea. Invest Ophthalmol Vis Sci 2000; 41: S832.
Ambati BK et al. Angiostatin inhibits and regresses corneal neovascularization. Arch Ophthalmol 2002; 120: 1063–1068.
Wu PC et al. Inhibition of experimental angiogenesis of cornea by somatostatin. Graefes Arch Clin Exp Ophthalmol 2003; 241: 63–69.
Shafiee A et al. Inhibition of retinal angiogenesis by peptides derived from thrombospondin-1. Invest Ophthalmol Vis Sci 2000; 41: 2378–2388.
Bainbridge JW, Mistry AR, Thrasher AJ, Ali RR . Gene therapy for ocular angiogenesis. Clin Sci (London) 2003; 104: 561–575.
Yu WZ et al. Gene transfer of kringle 5 of plasminogen by electroporation inhibits corneal neovascularization. Ophthalmic Res 2003; 35: 239–246.
Nishimori H et al. A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Oncogene 1997; 15: 2145–2150.
Koh JT et al. Characterization of mouse brain-specific angiogenesis inhibitor 1 (BAI1) and phytanoyl-CoA alpha-hydroxylase-associated protein 1, a novel BAI1-binding protein. Mol Brain Res 2001; 87: 223–237.
Kee HJ et al. Expression of brain-specific angiogenesis inhibitor 2 (BAI2) in normal and ischemic brain: involvement of BAI2 in the ischemia-induced brain angiogenesis. J Cereb Blood Flow Metab 2002; 22: 1052–1067.
Koh JT et al. Extracellular fragment of brain-specific angiogenesis inhibitor 1 suppresses endothelial cell proliferation by blocking αvβ5 integrin. Exp Cell Res 2004; 294: 172–184.
Ko HM et al. Nuclear factor kappaB dependency of platelet-activating factor-induced angiogenesis. Cancer Res 2002; 62: 1809–1814.
Benelli U, Ross JR, Nardi M, Klintworth GK . Corneal neovascularization induced by xenografts or chemical cautery. Inhibition by cyclosporin A. Invest Ophthalmol Vis Sci 1997; 38: 274–282.
Joussen AM et al. Inhibition of inflammatory corneal aniogenensis by TNP-470. Invest Ophthalmol Vis Sci 2001; 42: 2510–2516.
Phillips K et al. Effect of prednisolone and medroxyprogesterone on corneal wound healing, ulceration, and neovascularization. Arch Ophthalmol 1983; 101: 640–643.
Hayness WL, Proia AD, Klintworth GK . Effect of inhibitors of arachidonic acid metabolism on corneal neovascularization in the rat. Invest Ophthalmol Vis Sci 1989; 30: 1588–1593.
Kruse FE et al. Thalidomide inhibits corneal angiogenesis induced by vascular endothelial growth factor. Graefes Arch Clin Exp Ophthalmol 1998; 236: 461–466.
Joussen AM, Kruse FE, Volcker HE, Kirchhof B . Topical application of methotrexate for inhibition of corneal angiogenesis. Graefes Arch Clin Exp Ophthalmol 1999; 237: 920–927.
Kobayashi N et al. Suppression of corneal neovascularization by culture supernatant of human amniotic cells. Cornea 2002; 21: 62–67.
Gorrin-Rivas MJ et al. Mouse macrophage metalloelastase gene transfer into a murine melanoma suppresses primary tumor growth by halting angiogenesis. Clin Cancer Res 2000; 6: 1647–1654.
Matsuda KM et al. A novel strategy for tumor angiogenesis-targeted gene therapy: generation of angiostatin from endogenous plasminigen by protease gene transfer. Cancer Gene Ther 2000; 7: 589–596.
Stechschulte S et al. Rapid ocular angiogenic control via naked DNA delivery to cornea. Invest Ophthalmol Vis Sci 2001; 42: 1975–1979.
Plate KH . Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 1999; 58: 313–320.
Van Meir EG et al. Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet 1994; 8: 171–176.
Brooks PC et al. Integrin alphav beta3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994; 79: 1157–1164.
Friedlander M et al. Definition of two angiogenic pathways by distinct alphav integrins. Science 1995; 270: 1500–1502.
Friedlander M et al. Involvement of integrins alphav beta3 and alphav beta5 in ocular neovascular diseases. Proc Natl Acad Sci USA 1996; 93: 9764–9769.
Erdreich-Epstein A et al. Integrins alpha(v)beta3 and alpha(v)beta5 are expressed by endothelium of high-risk neuroblastoma and their inhibition is associated with increased endogenous ceramide. Cancer Res 2001; 60: 712–721.
Kook H et al. Nitric oxide-dependent cytoskeletal changes and inhibition of endothelial cell migration contribute to the suppression of angiogenesis by RAD50 gene transfer. FEBS Lett 2003; 553: 56–62.
Acknowledgements
We thank Song Eun Lee for assisance with immunohistochemistry and Jennifer Macke for assistance in preparing the text. This work was supported by the Korea Science & Engineering Foundation through the Medical Research Center for Gene Regulation (R13-2002-013-02000-0) at Chonnam National University.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yoon, K., Ahn, K., Lee, J. et al. Lipid-mediated delivery of brain-specific angiogenesis inhibitor 1 gene reduces corneal neovascularization in an in vivo rabbit model. Gene Ther 12, 617–624 (2005). https://doi.org/10.1038/sj.gt.3302442
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3302442
- Springer Nature Limited
Keywords
This article is cited by
-
Therapeutic Strategies for Corneal Wound Angiogenesis
Current Pathobiology Reports (2020)
-
Anti-neovascular effect of chondrocyte-derived extracellular matrix on corneal alkaline burns in rabbits
Graefe's Archive for Clinical and Experimental Ophthalmology (2014)
-
A proprotein convertase/MMP-14 proteolytic cascade releases a novel 40 kDa vasculostatin from tumor suppressor BAI1
Oncogene (2012)
-
Emerging roles for the BAI1 protein family in the regulation of phagocytosis, synaptogenesis, neurovasculature, and tumor development
Journal of Molecular Medicine (2011)
-
Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model
Gene Therapy (2009)