Somatostatin inhibits IGF-1 mediated induction of VEGF in human retinal pigment epithelial cells

• Published in: Experimental eye research 2004-10, Vol.79 (4), p.465-476
• Main Authors: Sall, Jeffrey W., Klisovic, Dino D., O'Dorisio, M.Sue, Katz, Steven E.
• Format: Article
• Language: English
• Subjects: Cells, Cultured; choroidal neovascularization; diabetic retinopathy; Dose-Response Relationship, Drug; Gene Expression Regulation - drug effects; Humans; IGF-1R; Insulin-Like Growth Factor I - antagonists & inhibitors; Insulin-Like Growth Factor I - pharmacology; macular degeneration; octreotide; Octreotide - pharmacology; Phosphorylation - drug effects; Pigment Epithelium of Eye - cytology; Pigment Epithelium of Eye - drug effects; Pigment Epithelium of Eye - metabolism; Receptor, IGF Type 1 - biosynthesis; Receptor, IGF Type 1 - genetics; Receptors, Somatostatin - biosynthesis; Receptors, Somatostatin - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Somatostatin - pharmacology; somatostatin receptor; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; VEGF
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2004.06.007

Neovascularization stimulated by IGF-1 mediated induction of vascular endothelial growth factor (VEGF) is one of the leading causes of blindness in humans. It plays a central role in the pathogenesis of proliferative diabetic retinopathy (DR), neovascular glaucoma, exudative age-related macular degeneration (AMD) and retinopathy of prematurity. Neovascularization is a multi-step process that involves complex interactions of a variety of mitogenic factors such as VEGF and IGF-I which are produced locally in the human eye by a variety of cells including retinal pigment epithelial (RPE) cells, retinal capillary pericytes, endothelial cells, Mueller cells and ganglion cells. We hypothesized that somatostatin would inhibit the IGF-1 signal transduction pathway in RPE cells, resulting in decreased VEGF production. We have observed expression of somatostatin receptor protein in retinal pigment epithelial (RPE) cells of the human eye using immunohistochemistry and have confirmed expression of somatostatin receptors in cultured human RPE cells using reverse transcriptase-PCR. IGF-1 induced a dose dependent increase in IGF-1R phosphorylation and in VEGF mRNA levels in cultured human RPE cells. Somatostatin and octreotide, a somatostatin analogue, inhibited IGF-1 receptor (IGF-1R) phosphorylation and decreased VEGF production. Both IGF-1R phosphorylation and accumulation of VEGF mRNA were inhibited by physiological levels of somatostatin and octreotide (1 nM). These results demonstrate somatostatin and octreotide mediated attenuation of both IGF-1R signal transduction and VEGF mRNA accumulation via somatostatin receptor type 2 (sst2). Furthermore, these data suggest a rationale for the use of octreotide as a prophylactic and therapeutic option in disease states that cause ocular neovascularization.