title: VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston 02114, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Usui
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamashiro
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kaji
authors.forename: Shiro
authors.initials: S
authors.lastname: Amano
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ogura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Hida
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Oguchi
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Evangelos S
authors.initials: ES
authors.lastname: Gragoudas
authors.forename: Yin-Shan
authors.initials: YS
authors.lastname: Ng
authors.forename: Patricia A
authors.initials: PA
authors.lastname: D'Amore
authors.forename: David T
authors.initials: DT
authors.lastname: Shima
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Adamis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002448:Cell Adhesion / Q000502:physiology; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D018919:Neovascularization, Physiologic; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D015861:Retinal Neovascularization / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels; D013601:T-Lymphocytes / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D020033:Protein Isoforms; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor