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Originally published In Press as doi:10.1167/iovs.08-3044 on April 1, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:4410-4415.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3044
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Involvement of Hyaluronan and Its Receptor CD44 with Choroidal Neovascularization

Hiroshi Mochimaru,1,2 Eri Takahashi,3,4 Nobuo Tsukamoto,5 Junichiro Miyazaki,5 Tomonori Yaguchi,5 Takashi Koto,1,2 Toshihide Kurihara,1,2 Kousuke Noda,1,2 Yoko Ozawa,1,2 Takatsugu Ishimoto,3 Yutaka Kawakami,5 Hidenobu Tanihara,4 Hideyuki Saya,3 Susumu Ishida,1,2,6 and Kazuo Tsubota2

1From the Laboratory of Retinal Cell Biology, the 2Department of Ophthalmology, the Divisions of 3Gene Regulation and 5Cellular Signaling, Institute for Advanced Medical Research, and the 6Inaida Endowed Department of Anti-Aging Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and the 4Department of Ophthalmology and Visual Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

PURPOSE. CD44 is a cell-surface adhesion molecule and receptor for hyaluronan (HA), one of the major extracellular matrix components. The purpose of the present study was to clarify a role of HA and CD44 in the development of choroidal neovascularization (CNV).

METHODS. Laser photocoagulation was used to induce CNV in C57BL/6 mice or CD44-deficient mice. The mRNA expression of CD44 and HA synthase (HAS)-2 in the retinal pigment epithelium (RPE)–choroid complex was evaluated by DNA microarray and real-time RT-PCR analyses 3 days after laser treatment. HA synthesis and CD44 expression were examined by immunohistochemistry 1 week after photocoagulation. Mice with laser-induced CNV were systemically administered the HA synthesis inhibitor 4-methylumbelliferone (MU) or an anti-CD44-neutralizing antibody. The response of CNV was analyzed by volumetric measurements 1 week after photocoagulation. Macrophage infiltration into CNV lesions was evaluated by real-time RT-PCR for F4/80 3 days after laser-induced injury.

RESULTS. The induction of CNV led to a significant increase in expression of CD44 and HAS2 mRNA. HA and CD44 were immunopositive in the CNV lesions. Compared with vehicle treatment, the systemic application of MU significantly attenuated CNV volume in a dose-dependent fashion, together with macrophage infiltration into the lesions. Consistently, antibody-based blockade of CD44 resulted in a significant reduction of CNV volume, compared with the isotype control. In contrast, genetic ablation of CD44 significantly augmented CNV formation together with HA accumulation and macrophage infiltration, compared with wild-type mice.

CONCLUSIONS. These results indicate a significant role of HA and its receptor CD44 in the development of CNV.






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