VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization
| Autor: | Susumu Ishida, Yoshihisa Oguchi, Anthony P. Adamis, Yin-Shan Ng, Yuichi Kaji, Jayakrishna Ambati, Joan W. Miller, Shiro Amano, Patricia A. D'Amore, Tetsuo Hida, Kenji Yamashiro, David T. Shima, Tomohiko Usui, Yuichiro Ogura, Evangelos S. Gragoudas |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Cellular immunity retina genetic structures Angiogenesis T-Lymphocytes Endothelial Growth Factors Retinal Neovascularization Monocytes Neovascularization chemistry.chemical_compound angiogenesis Mice Ischemia Leukocytes Immunology and Allergy Protein Isoforms Mice Knockout Lymphokines Vascular Endothelial Growth Factors VEGF Vascular endothelial growth factor Vascular endothelial growth factor A Intercellular Signaling Peptides and Proteins Female medicine.symptom leukocyte Recombinant Fusion Proteins Immunology Neovascularization Physiologic Inflammation Biology medicine Cell Adhesion Animals Cell adhesion Brief Definitive Report Retinal Vessels Retinal Receptors Interleukin-2 immunity eye diseases Rats Disease Models Animal Receptors Vascular Endothelial Growth Factor chemistry Animals Newborn Cancer research sense organs |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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