IOVS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

(Investigative Ophthalmology and Visual Science. 2006;47:5022-5031.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-1236
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Maines, L. W.
Right arrow Articles by Smith, C. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maines, L. W.
Right arrow Articles by Smith, C. D.

Pharmacologic Manipulation of Sphingosine Kinase in Retinal Endothelial Cells: Implications for Angiogenic Ocular Diseases

Lynn W. Maines,1 Kevin J. French,1 Ellen B. Wolpert,2 David A. Antonetti,2,3 and Charles D. Smith1,4

1From the Apogee Biotechnology Corporation, Hershey, Pennsylvania; the 2Departments of Cellular and Molecular Physiology and 3Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania; and the 4Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina.

PURPOSE. The increased vascular permeability and pathogenic angiogenesis observed in diabetic retinopathy are induced, at least in part, by local inflammation and vascular endothelial growth factor (VEGF). Therefore, inhibition of signaling from VEGF and tumor necrosis factor-{alpha} (TNF{alpha}) is a promising approach to the treatment of this disease, as well as ocular diseases with similar etiologies, including age-related macular degeneration. A growing body of evidence demonstrates that sphingosine kinase (SK) plays an important role in cellular proliferation and angiogenesis. This study was undertaken to examine the effects of SK inhibitors on the responses of retinal endothelial cells (RECs) to VEGF and TNF{alpha} and their therapeutic efficacy in a diabetic retinopathy model.

METHODS. The expression and function of SK in bovine and human RECs were examined by immunoblot analysis. The involvement of SK in mediating responses to VEGF and TNF{alpha} was examined by using pharmacologic inhibitors of SK in cellular and in vivo assays, including a 3-month streptozotocin-induced diabetic retinopathy model in rats.

RESULTS. SK was present and active in human and bovine RECs, and SK activity in these cells was stimulated by VEGF. Inhibitors of SK blocked VEGF-induced production of sphingosine 1-phosphate and markedly attenuated VEGF-induced proliferation and migration of RECs. In addition, SK inhibitors were shown to block TNF{alpha}-induced expression of adhesion proteins, suppress VEGF-induced vascular leakage in an in vivo mouse model, and reduce retinal vascular leakage in the rat diabetic retinopathy model.

CONCLUSIONS. Overall, these studies demonstrate that inhibitors of SK attenuate the effects of proliferative and inflammatory stimuli on RECs both in vitro and in vivo, and so could be significant therapeutics in the treatment of diabetic retinopathy.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2006 by the Association for Research in Vision and Ophthalmology