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Jennifer L. Wilkinson-Berka, Daria Jones, George Taylor, Kassie Jaworski, Darren J. Kelly, Steve B. Ludbrook, Robert N. Willette, Sanjay Kumar, Richard E. Gilbert; SB-267268, a Nonpeptidic Antagonist of αvβ3 and αvβ5 Integrins, Reduces Angiogenesis and VEGF Expression in a Mouse Model of Retinopathy of Prematurity. Invest. Ophthalmol. Vis. Sci. 2006;47(4):1600-1605. doi: 10.1167/iovs.05-1314.
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purpose. To determine whether SB-267268, a nonpeptidic antagonist of the αvβ3 and αvβ5 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 αvβ3 and αvβ5. SB-267268 inhibited the attachment of αvβ3-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 αvβ3 and αvβ5 integrins is effective in ROP and may be a suitable anti-angiogenic therapy for other ischemic retinal pathologies.
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