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.
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4 August 2003
Brief Definitive Report|
August 04 2003
VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization
Susumu Ishida,
Susumu Ishida
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
3Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan
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Tomohiko Usui,
Tomohiko Usui
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
4Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
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Kenji Yamashiro,
Kenji Yamashiro
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
5Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
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Yuichi Kaji,
Yuichi Kaji
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
4Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
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Shiro Amano,
Shiro Amano
4Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
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Yuichiro Ogura,
Yuichiro Ogura
6Department of Ophthalmology, Nagoya City University Medical School, Nagoya 467-8601, Japan
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Tetsuo Hida,
Tetsuo Hida
7Kyorin Eye Center, Mitaka 181-8611, Japan
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Yoshihisa Oguchi,
Yoshihisa Oguchi
3Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan
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Jayakrishna Ambati,
Jayakrishna Ambati
8Department of Ophthalmology, University of Kentucky, Lexington, KY 40517
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Joan W. Miller,
Joan W. Miller
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
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Evangelos S. Gragoudas,
Evangelos S. Gragoudas
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
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Yin-Shan Ng,
Yin-Shan Ng
2Department of Pathology and Ophthalmology, Schepens Eye Research Institute,Harvard Medical School, Boston, MA 02114
9Eyetech Research Center, Woburn, MA 01801
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Patricia A. D'Amore,
Patricia A. D'Amore
2Department of Pathology and Ophthalmology, Schepens Eye Research Institute,Harvard Medical School, Boston, MA 02114
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David T. Shima,
David T. Shima
9Eyetech Research Center, Woburn, MA 01801
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Anthony P. Adamis
Anthony P. Adamis
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
9Eyetech Research Center, Woburn, MA 01801
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Susumu Ishida
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
3Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan
Tomohiko Usui
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
4Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
Kenji Yamashiro
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
5Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
Yuichi Kaji
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
4Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
Shiro Amano
4Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
Yuichiro Ogura
6Department of Ophthalmology, Nagoya City University Medical School, Nagoya 467-8601, Japan
Tetsuo Hida
7Kyorin Eye Center, Mitaka 181-8611, Japan
Yoshihisa Oguchi
3Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan
Jayakrishna Ambati
8Department of Ophthalmology, University of Kentucky, Lexington, KY 40517
Joan W. Miller
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
Evangelos S. Gragoudas
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
Yin-Shan Ng
2Department of Pathology and Ophthalmology, Schepens Eye Research Institute,Harvard Medical School, Boston, MA 02114
9Eyetech Research Center, Woburn, MA 01801
Patricia A. D'Amore
2Department of Pathology and Ophthalmology, Schepens Eye Research Institute,Harvard Medical School, Boston, MA 02114
David T. Shima
9Eyetech Research Center, Woburn, MA 01801
Anthony P. Adamis
1Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary
9Eyetech 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: [email protected]
S. Ishida, T. Usui, and K. Yamashiro contributed equally to this work.
Received:
November 21 2002
Revision Received:
May 13 2003
Accepted:
May 23 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 198 (3): 483–489.
Article history
Received:
November 21 2002
Revision Received:
May 13 2003
Accepted:
May 23 2003
Citation
Susumu Ishida, Tomohiko Usui, Kenji Yamashiro, Yuichi Kaji, Shiro Amano, Yuichiro Ogura, Tetsuo Hida, Yoshihisa Oguchi, Jayakrishna Ambati, Joan W. Miller, Evangelos S. Gragoudas, Yin-Shan Ng, Patricia A. D'Amore, David T. Shima, Anthony P. Adamis; VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization . J Exp Med 4 August 2003; 198 (3): 483–489. doi: https://doi.org/10.1084/jem.20022027
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