Expression, localization, and functional coupling of the somatostatin receptor subtype 2 in a mouse model of oxygen-induced retinopathy.
Purpose. In the mouse model of oxygen-induced retinopathy (OIR), somatostatin-14 (SRIF) acting at the SRIF receptor subtype 2 (sst(2)) inhibits angiogenic responses to hypoxia through a downregulation of vascular endothelial growth factor. Information about where SRIF-sst(2) interactions take place is lacking, and downstream effectors mediating SRIF-sst(2) antiangiogenic actions are unknown. Methods. In the OIR model, retinal expression of SRIF was evaluated with RT-PCR and radioimmunoassay. The bindings of [(125)I]LTT-SRIF-28 and [(125)I]Tyr(3)-octreotide were measured in coronal sections of the eye. With Western blot analysis, the authors evaluated the levels of sst(2A) 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 sst(2) agonist octreotide or with the sst(2) antagonist D-Tyr(8) cyanamid 154806 (CYN). Retinal localization of sst(2A) was assessed by single and double immunohistochemistry with an endothelial cell marker. Results. In the hypoxic retina, both SRIF and sst(2) levels as well as [(125)I]Tyr(3)-octreotide binding were downregulated. In addition, sst(2A) 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. Conclusions. These data suggest that sst(2) 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 sst(2)-selective ligands in the treatment of proliferative retinopathies and indicate STAT3 as an additional target for a novel therapeutic approach.
Dal Monte
Massimo
M
Dipartimento di Biologia, Università di Pisa, Pisa, Italy.
Ristori
Chiara
C
Videau
Catherine
C
Loudes
Catherine
C
Martini
Davide
D
Casini
Giovanni
G
Epelbaum
Jacques
J
Bagnoli
Paola
P
D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015282:Octreotide / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010100:Oxygen / Q000633:toxicity; D011863:Radioimmunoassay; D017481:Receptors, Somatostatin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism; D012178:Retinopathy of Prematurity / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism*
C403089:CYN 154806; D009842:Oligopeptides; D017481:Receptors, Somatostatin; D050796:STAT3 Transcription Factor; C492049:Sstr2 protein, mouse; C494087:Stat3 protein, mouse; D013004:Somatostatin; D015282:Octreotide; D010100:Oxygen