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Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease

Nature Medicine volume 9, pages 781–788 (2003)Cite this article

Abstract

Retinal 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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Figure 1: Temporal and spatial correlation of leukocyte adhesion with retinal vascular remodeling.
Figure 2: Suppression of leukocyte adhesion and vascular pruning with CD18 blockade.
Figure 3: Suppression of vascular pruning with FasL blockade.
Figure 4: Temporal and spatial correlation of adherent leukocytes with ischemic retinopathy.
Figure 5: Suppression of vaso-obliteration with CD18 blockade.
Figure 6: Suppression of vaso-obliteration and in vitro endothelial cell apoptosis with FasL blockade.

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Acknowledgements

This work was funded by the Roberta W. Siegel Fund, NIH EY12611 and EY11627, the Juvenile Diabetes Foundation, the Falk Foundation and the Iaccoca Foundation.

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Author notes

  1. Susumu Ishida and Kenji Yamashiro: These authors contributed equally to this work.

Authors and Affiliations

  1. Angiogenesis/Retina Research Laboratory, Massachusetts Eye & Ear Infirmary, Harvard Medical School, 325 Cambridge Street, Boston, 02114, Massachusetts, USA

    Susumu Ishida, Kenji Yamashiro, Tomohiko Usui, Yuichi Kaji & Anthony P Adamis

  2. Department of Ophthalmology, Keio University School of Medicine, 35 Shinano, Shinjuku, Tokyo, 160-8582, Japan

    Susumu Ishida & Yoshihisa Oguchi

  3. Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Kawahara, Shogoin, Sakyo, Kyoto, 606-8507, Japan

    Kenji Yamashiro & Yoshihito Honda

  4. Department of Ophthalmology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan

    Tomohiko Usui & Yuichi Kaji

  5. Department of Ophthalmology, Nagoya City University Medical University, 1 Kawasumi, Mizuho, Nagoya, Aichi, 467-8601, Japan

    Yuichiro Ogura

  6. Kyorin Eye Center, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan

    Tetsuo Hida

  7. Eyetech Research Center, 42 Cummings Park, Woburn, 01801, Massachusetts, USA

    Anthony P Adamis

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  1. Susumu Ishida
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Correspondence to Anthony P Adamis.

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A.P.A. is the chief scientific officer of Eyetech Pharmaceuticals.

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Ishida, S., Yamashiro, K., Usui, T. et al. Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease. Nat Med 9, 781–788 (2003). https://doi.org/10.1038/nm877

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