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Massimo Dal Monte, Chiara Ristori, Catherine Videau, Catherine Loudes, Davide Martini, Giovanni Casini, Jacques Epelbaum, Paola Bagnoli; Expression, Localization, and Functional Coupling of the Somatostatin Receptor Subtype 2 in a Mouse Model of Oxygen-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(4):1848-1856. doi: 10.1167/iovs.09-4472.
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In the mouse model of oxygen-induced retinopathy (OIR), somatostatin-14 (SRIF) acting at the SRIF receptor subtype 2 (sst2) inhibits angiogenic responses to hypoxia through a downregulation of vascular endothelial growth factor. Information about where SRIF-sst2 interactions take place is lacking, and downstream effectors mediating SRIF-sst2 antiangiogenic actions are unknown.
In the OIR model, retinal expression of SRIF was evaluated with RT-PCR and radioimmunoassay. The bindings of [125I]LTT-SRIF-28 and [125I]Tyr3-octreotide were measured in coronal sections of the eye. With Western blot analysis, the authors evaluated the levels of sst2A and the expression and activity of the signal transducer and activator of transcription (STAT)3. The analysis of STAT3 was performed in hypoxic mice treated with the sst2 agonist octreotide or with the sst2 antagonist D-Tyr8 cyanamid 154806 (CYN). Retinal localization of sst2A was assessed by single and double immunohistochemistry with an endothelial cell marker.
In the hypoxic retina, both SRIF and sst2 levels as well as [125I]Tyr3-octreotide binding were downregulated. In addition, sst2A immunostaining was decreased in the neuroretina but was increased in capillaries. Hypoxia increased both the expression and the activity of STAT3. This increase was inhibited by octreotide but was strengthened by CYN.
These data suggest that sst2 expressed by capillaries may be responsible for the antiangiogenic effects of SRIF and that downstream effectors in this action include the transcription factor STAT3. These results support the possibility of using sst2-selective ligands in the treatment of proliferative retinopathies and indicate STAT3 as an additional target for a novel therapeutic approach.
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