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Antiangiogenic Role of Somatostatin Receptor 2 in a Model of Hypoxia-Induced Neovascularization in the Retina: Results from Transgenic Mice

¹From the Dipartimento di Biologia, Università di Pisa, Via san Zeno, Pisa, Italy; ²Dipartimento di Scienze Ambientali, Università della Tuscia, Largo dell’Università, Viterbo, Italy.

PURPOSE. To determine whether the somatostatin receptor 2 (sst₂) influences angiogenesis and its associated factors in a model of hypoxia-induced retinal neovascularization.

METHODS. sst₁-knockout (KO) mice, in which sst₂ is overexpressed and overfunctional, and sst₂-KO mice were used. Angiogenesis was evaluated in fluorescein-perfused retinas. Angiogenesis-associated factors were determined by RT-PCR and immunohistochemistry.

RESULTS. Retinal neovascularization was increased in sst₂-KO mice, but remained unchanged in sst₁-KO compared with wild-type (WT) mice. Retinal levels of sst₂ mRNA were not affected by hypoxia. Normoxic levels of angiogenesis regulators were similar in WT and KO retinas except for mRNA levels of IGF-1, Ang-2, and its receptor Tie-2. In WT, hypoxia induced an increase in mRNA levels of (1) VEGF and its receptors, (2) IGF-1R, and (3) Ang-2 and Tie-2. The increase in VEGF and IGF-1R mRNAs was more pronounced after sst₂ loss, but was less pronounced when sst₂ was overexpressed. In addition, in hypoxic retinas, sst₂ loss increased IGF-1 mRNA, whereas it decreased Ang-1, Tie-1, and Tie-2 mRNA levels. Moreover, Tie-1 mRNA increased when sst₂ was overexpressed. Immunohistochemistry confirmed the results in hypoxic retinas on increased expression of VEGF, IGF-1, and their receptors after sst₂ loss. It also allowed the localization of these factors to specific retinal cells. In this respect, VEGFR-2, IGF-1, and IGF-1R were localized to Müller cells.

CONCLUSIONS. These results suggest that sst₂ may be protective against angiogenesis. The immediate clinical importance lies in the establishment of a potential pharmacological target based on sst₂ pharmacology.