SB–267268 a Non–Peptidic Antagonist of Alphavbeta3 and Alphavbeta5 Integrins Reduces Angiogenesis and VEGF Expression in a Mouse Model of Retinopathy of Prematurity

Abstract

Purpose: : . To determine if SB–267268, a non–peptidic antagonist of the alphavbeta3 and alphavbeta5 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 alphavbeta3 and alphavbeta5. SB–267268 inhibited the attachment of αvß3 transfected HEK293 cells to microtiter plate wells pre–coated with RGD–containing matrix proteins, and vitronectin–mediated human and rat aortic smooth muscle cell migration. At postnatal day 12, C57BL/6 mice were exposed to 80% oxygen for 7 days followed by 7 days in room air (angiogenic period). Between postnatal days (P) 12–17, ROP mice were administered sterile saline (vehicle 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 P12–17. In at least 3 randomly chosen paraffin sections from each eye the number of blood vessel profiles (BVPs) in the inner retina were counted. In situ hybridisation for VEGF and VEGFR–2 was performed on at least 8 randomly chosen paraffin sections from each eye.

Results: : . SB–267268 reduced pathological angiogenesis in ROP mice by approximately 50%, and had no effect on developmental retinal angiogenesis in shams. Both VEGF and VEGFR–2 mRNA were up–regulated in the inner retina of ROP mice and reduced with SB–267268.

Conclusions: : . Non–peptidic inhibition of alphavbeta3 and alphavbeta5 integrins is effective in ROP and may be a suitable anti–angiogenic therapy for other ischemic retinal pathologies.

Keywords: retinopathy of prematurity • neovascularization • cell adhesions/cell junctions