The Journal of Experimental Medicine
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Published 4 August 2003. doi:10.1084/jem.20022027
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© Rockefeller University Press, 0022-1007/2003/8/483 $5.00
The Journal of Experimental Medicine, Volume 198, Number 3, 483-489

Brief Definitive Report

VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization

Susumu Ishida1,3, Tomohiko Usui1,4, Kenji Yamashiro1,5, Yuichi Kaji1,4, Shiro Amano4, Yuichiro Ogura6, Tetsuo Hida7, Yoshihisa Oguchi3, Jayakrishna Ambati8, Joan W. Miller1, Evangelos S. Gragoudas1, Yin-Shan Ng2,9, Patricia A. D'Amore2, David T. Shima9 and Anthony P. Adamis1,9

1 Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
2 Department of Pathology and Ophthalmology, Schepens Eye Research Institute,Harvard Medical School, Boston, MA 02114
3 Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan
4 Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
5 Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
6 Department of Ophthalmology, Nagoya City University Medical School, Nagoya 467-8601, Japan
7 Kyorin Eye Center, Mitaka 181-8611, Japan
8 Department of Ophthalmology, University of Kentucky, Lexington, KY 40517
9 Eyetech Research Center, Woburn, MA 01801

Address correspondence to Anthony P. Adamis, Eyetech Research Center, 42 Cummings Park, Woburn, MA 01801. Phone: 781-935-3937; Fax: 781-935-9083; email: tony.adamis{at}eyetk.com

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte–mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.

Key Words: retina • angiogenesis • VEGF • leukocyte • immunity


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