Nature Medicine
9, 781 - 788 (2003)
Published online: 5 May 2003; | doi:10.1038/nm877
Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in diseaseSusumu Ishida1, 2, 8, Kenji Yamashiro1, 3, 8, Tomohiko Usui1, 4, Yuichi Kaji1, 4, Yuichiro Ogura5, Tetsuo Hida6, Yoshihito Honda3, Yoshihisa Oguchi2
& Anthony P Adamis1, 71
Angiogenesis/Retina Research Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, 325 Cambridge Street, Boston, Massachusetts 02114, USA. 2
Department of Ophthalmology, Keio University School of Medicine, 35 Shinano, Shinjuku, Tokyo 160-8582, Japan. 3
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Kawahara, Shogoin, Sakyo, Kyoto 606-8507, Japan. 4
Department of Ophthalmology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. 5
Department of Ophthalmology, Nagoya City University Medical University, 1 Kawasumi, Mizuho, Nagoya, Aichi 467-8601, Japan. 6
Kyorin Eye Center, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. 7
Eyetech Research Center, 42 Cummings Park, Woburn, Massachusetts 01801, USA. 8
These authors contributed equally to this work.
Correspondence should be addressed to Anthony P Adamis tony.adamis@eyetk.comRetinal ischemia can cause vision-threatening pathological neovascularization. The mechanisms of retinal ischemia are not fully understood, however. Here we have shown that leukocytes prune the retinal vasculature during normal development and obliterate it in disease. Beginning at postnatal day 5 (P5) in the normal rat, vascular pruning began centrally and extended peripherally, leaving behind a less dense, smaller-caliber vasculature. The pruning was correlated with retinal vascular expression of intercellular adhesion molecule-1 (ICAM-1) and coincided with an outward-moving wave of adherent leukocytes composed in part of cytotoxic T lymphocytes. The leukocytes adhered to the vasculature through CD18 and remodeled it through Fas ligand (FasL)-mediated endothelial cell apoptosis. In a model of oxygen-induced ischemic retinopathy, this process was exaggerated. Leukocytes used CD18 and FasL to obliterate the retinal vasculature, leaving behind large areas of ischemic retina. In vitro, T lymphocytes isolated from oxygen-exposed neonates induced a FasL-mediated apoptosis of hyperoxygenated endothelial cells. Targeting these pathways may prove useful in the treatment of retinal ischemia, a leading cause of vision loss and blindness.
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