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Endogenous endostatin inhibits choroidal neovascularization

Alexander G. Marneros^*,1, Haicheng She, Hadi Zambarakji, Hiroya Hashizume, Edward J. Connolly, Ivana Kim, Evangelos S. Gragoudas, Joan W. Miller and Bjorn R. Olsen^*

^* Department of Developmental Biology, Harvard School of Dental Medicine, and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA;

Angiogenesis Laboratory and Retina Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA; and

Division of Microscopic Anatomy and Bioimaging, Niigata University Postgraduate School of Medical and Dental Sciences, Niigata City, Japan

¹Correspondence: Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave., Boston, MA 02115, USA. E-mail: alexander_marneros{at}yahoo.com

Endostatin, a fragment of the basement membrane component collagen XVIII, exhibits antiangiogenic properties in vitro and in vivo when high doses are administered. It is not known whether endogenous endostatin at physiological levels has a protective role as an inhibitor of pathological angiogenesis, such as choroidal neovascularization (CNV) in age-related macular degeneration. Using a laser injury model, we induced CNV in mice lacking collagen XVIII/endostatin and in control mice. CNV lesions in mutant mice were 3-fold larger than in control mice and showed increased vascular leakage. These differences were independent of age-related changes at the choroid-retina interface. Ultrastructural analysis of the choroidal vasculature in mutant mice excluded morphological vascular abnormalities as a cause for the larger CNV lesions. When recombinant endostatin was administered to collagen XVIII/endostatin-deficient mice, CNV lesions were similar to those seen in control mice. In control mice treated with recombinant endostatin, CNV lesions were almost undetectable. These findings demonstrate that endogenous endostatin is an inhibitor of induced angiogenesis and that administration of endostatin potently inhibits CNV growth and vascular leakage. Endostatin may have a regulatory role in the pathogenesis of CNV and could be used therapeutically to inhibit growth and leakage of CNV lesions.—Marneros, A. G., She, H., Zambarakji, H., Hashizume, H., Connolly, E. J., Kim, I., Gragoudas, E. S., Miller, J. W., Olsen, B. R. Endogenous endostatin inhibits choroidal neovascularization.

Key Words: angiogenesis • collagen XVIII • Bruch’s membrane • age-related macular degeneration