Effects of Somatostatin Analogues on Retinal Angiogenesis in a Mouse Model of Oxygen-Induced Retinopathy: Involvement of the Somatostatin Receptor Subtype 2

PURPOSE. To determine whether selective activation or blockade of the somatostatin (SRIF) receptor 2 (sst(2)) with two SRIF analogues, octreotide and D-Tyr(8) cyanamid 154806 (CYN), influences retinal vascularization and levels of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and -2 in a mouse model of oxygen-induced retinopathy (OIR). METHODS. Wild-type (WT), sst(1)-knockout (KO), and sst(2)-KO mice were used. The OIR model was used to test the effects of octreotide and CYN administered subcutaneously. Retinopathy was assessed by a retinal scoring system using fluorescein-perfused retinal wholemounts. Retinal levels of VEGF, VEGFR-1, and -2 were evaluated with quantitative RT-PCR, Western blot, and ELISA. RESULTS. In both WT and sst(1)-KO mice, OIR-induced neovascularization was reduced by octreotide, whereas it was increased by CYN. No effects of octreotide and CYN on retinal neovascularization were observed in sst(2)-KO retinas. Hypoxia upregulated the expression of VEGF and its receptors. Compared with WT retinas, the increase in VEGF, but not in VEGF receptors, was less pronounced in sst(1)-KO retinas in which sst(2) is known to be overexpressed. The hypoxia-induced increase in VEGF and its receptors was affected by SRIF analogues, with ameliorative effects of octreotide and worsening effects of CYN, which were more pronounced in the presence of sst(2) overexpression. CONCLUSIONS. These data suggest that sst(2) regulates angiogenic responses to the hypoxic insult through a modulation of retinal levels of VEGF and its receptors. The present results further support the possibility of the use of sst(2)-selective ligands in the treatment of retinopathy. (Invest Ophthalmol Vis Sci. 2009; 50:3596-3606) DOI:10.1167/iovs.09-3412