Journal
EXPERIMENTAL EYE RESEARCH
Volume 88, Issue 3, Pages 367-377Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exer.2008.07.012
Keywords
sphingosine; anti-angiogenesis; age-related macular degeneration; choroidal neovascularization; fibrosis; animal model
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Funding
- NEI NIH HHS [R21 EY014818, R01 EY007739, R01 EY012601] Funding Source: Medline
- NIDDK NIH HHS [R01 DK090730] Funding Source: Medline
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The efficacy of novel monoclonal antibodies that neutralize the pro-angiogenic mediator, sphingosine-1-phosphate (S1P), were tested using in vitro and in vivo angiogenesis models, including choroidal neovascularization (CNV) induced by laser disruption of Bruch's membrane. S1P receptor levels in human brain choroid plexus endothelial cells (CPEC), human lung microvascular endothelial cells, human retinal vascular endothelial cells, and circulating endothelial progenitor cells were examined by semi-quantitative PCR. The ability of murine or humanized anti-SIP monoclonal antibodies (mAbs) to inhibit S1P-mediated microvessel tube formation by CPEC on Matrigel was evaluated and capillary density in subcutaneous growth factor-loaded Matrigel plugs was determined following anti-SIP treatment. SIP promoted in vitro capillary tube formation in CPEC consistent with the presence of cognate S1P(1-5) receptor expression by these cells and the SIP antibody induced a dose-dependent reduction in microvessel tube formation. In a murine model of laser-induced rupture of Bruch's membrane, SIP was detected in posterior cups of mice receiving laser injury, but not in uninjured controls. Intravitreous injection of anti-S1P mAbs dramatically inhibited CNV formation and sub-retinal collagen deposition in all treatment groups (p<0.05 compared to controls), thereby identifying SIP as a previously unrecognized mediator of angiogenesis and subretinal fibrosis in this model. These findings suggest that neutralizing SIP with anti-S1P mAbs may be a novel method of treating patients with exudative age-related macular degeneration by reducing angiogenesis and sub-retinal fibrosis, which are responsible for visual acuity loss in this disease. Published by Elsevier Ltd.
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