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R. Miller, S.-H. Min, M. E. Boulton, W. W. Hauswirth, M. B. Grant; Somatostatin and Its Receptors Play a Critical Role in Hypoxia-Regulated Retinal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4059.
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Retinal and vitreous levels of the anti-angiogenic neuropeptide somatostatin (SST) are reduced in patients with proliferative diabetic retinopathy. The natural peptide SST has an extremely short half-life when applied to the retina. While SST analogues with longer half lives have been developed their bioavailability is limited. The aim of this study was to determine whether AAV vector targeted delivery of SST to areas of retinal ischemia could enhance its efficacy and to investigate the expression of SST receptors in the oxygen-induced retinopathy (OIR) model so as to best target SST expression and delivery for inhibition of angiogenesis.
Mouse somatostatin packaged in an AAV vector (rAAV-2-CBA-SB-SST) was delivered by intraocular (OD) injection in C57BL/6 neonates (n=6). On postnatal day 7 (P7), pups were placed in 75% oxygen and then returned to room air on P12. Pups were euthanized on P17 and the extent of neovascularization was assessed by counting endothelial nuclei above the inner limiting membrane on retinal cross-sections. To determine the expression of the G-protein coupled SST receptors, SSTR1, 2A and 2B, retinal cryosections were immunostained with receptor subtype-specific antibodies.
Retinas from pups undergoing OIR model exhibited receptor specific immunolocalization in the retina. SSTR1 localized strongly to the preretinal vessels with weak staining in the ganglion cell and outer plexiform layers. Strong SSTR2A staining was observed in the outer plexiform layer, Muller cells and ganglion cells. Moderate SSTR2A staining was also observed in the RPE layer and in preretinal vessels. SSTR2B was strongly stained in the RPE layer and preretinal vessels but only weakly immunolocalized to the outer plexiform layer and Muller cells. Angiogenesis was decreased in AAV-SST injected eyes compared to control. The average number of endothelial nuclei of the control vs. AAV-SST injected eyes were 32 ± 2 nuclei and 20 ± 1 nuclei respectively, an inhibition of angiogenesis of 36 ± 3% (n=6) (p = 0.0003).
AAV vector expression of SST targeted to areas of hypoxia decreased preretinal angiogenesis. The strong co-localization of SSTR1 and 2B in preretinal vessels suggests that targeting specific SST receptors using subtype-specific SSTR agonists may represent the optimal therapeutic strategy.
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