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(Investigative Ophthalmology and Visual Science. 2006;47:1600-1605.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-1314
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SB-267268, a Nonpeptidic Antagonist of {alpha}vß3 and {alpha}vß5 Integrins, Reduces Angiogenesis and VEGF Expression in a Mouse Model of Retinopathy of Prematurity

Jennifer L. Wilkinson-Berka,1 Daria Jones,1 George Taylor,1 Kassie Jaworski,1 Darren J. Kelly,2 Steve B. Ludbrook,3 Robert N. Willette,3 Sanjay Kumar,3 and Richard E. Gilbert2,4

1From the Department of Physiology, University of Melbourne, Parkville, Victoria, Australia; 2Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, Australia; 3GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania; and 4Department of Medicine, University of Toronto, St. Michael’s Hospital, Toronto, Canada.

PURPOSE. To determine whether SB-267268, a nonpeptidic antagonist of the {alpha}vß3 and {alpha}vß5 integrins, attenuates angiogenesis in a murine model of retinopathy of prematurity (ROP) and alters the expression of vascular endothelial growth factor (VEGF) and its second receptor (VEGF-R2).

METHODS. In receptor binding, SB-267268 exhibited nanomolar potency for human, monkey, and murine {alpha}vß3 and {alpha}vß5. SB-267268 inhibited the attachment of {alpha}vß3-transfected HEK293 cells to microtiter plate wells precoated with RGD-containing matrix proteins, and vitronectin-mediated human and rat aortic smooth-muscle–cell migration. At postnatal day (P)12, C57BL/6 mice were exposed to 80% oxygen for 7 days followed by 7 days in room air (angiogenic period). Between P12 and P17, ROP mice were administered sterile saline (vehicle intraperitoneal [i.p.]) or SB-267268 (60 mg/kg bi-daily, i.p.). Shams were exposed to room air from P0 and administered either vehicle or SB-267268 during P12 to 17. In at least 3 randomly chosen paraffin sections from each eye, the number of blood vessel profiles in the inner retina were counted. In situ hybridization for VEGF and VEGFR-2 was performed on at least 8 randomly chosen paraffin sections from each eye.

RESULTS. SB-267268 reduced pathologic angiogenesis in ROP mice by approximately 50% and had no effect on developmental retinal angiogenesis in shams. Both VEGF and VEGFR-2 mRNA were upregulated in the inner retina of ROP mice and reduced with SB-267268.

CONCLUSIONS. Nonpeptidic inhibition of {alpha}vß3 and {alpha}vß5 integrins is effective in ROP and may be a suitable anti-angiogenic therapy for other ischemic retinal pathologies.




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