Regulation of vascular endothelial growth factor expression by insulin-like growth factor I

• Published in: Diabetes (New York, N.Y.) Vol. 46; no. 10; pp. 1619 - 1626
• Main Authors: PUNGLIA, R. S, LU, M, ADAMIS, A. P, HSU, J, KUROKI, M, TOLENTINO, M. J, KEOUGH, K, LEVY, A. P, LEVY, N. S, GOLDBERG, M. A, D'AMATO, R. J
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.1997
• Subjects: Animals; Antibodies - pharmacology; Biological and medical sciences; Blotting, Northern; Capillaries; Cell Division; Cell Hypoxia; Cell Line, Transformed; Culture Media, Conditioned; Endothelial Growth Factors - biosynthesis; Endothelial Growth Factors - genetics; Endothelium, Vascular - cytology; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Growth factors; Humans; Insulin-like growth factor 1; Insulin-like growth factor I; Insulin-Like Growth Factor I - pharmacology; Kinetics; Lymphokines - biosynthesis; Lymphokines - genetics; Mice; Neovascularization; Physiological aspects; Pigment Epithelium of Eye - metabolism; Promoter Regions, Genetic; Receptor, IGF Type 1 - antagonists & inhibitors; Retina; RNA, Messenger - metabolism; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vertebrates: nervous system and sense organs; Eye; Visual system; Angiogenesis; Insulin like growth factor; Vascular endothelium growth factor; Cell line; Epithelial cell; Retina; Neovascularization; Gene expression
• ISSN: 0012-1797; 1939-327X; 0012-1797
• DOI: 10.2337/diabetes.46.10.1619

Regulation of vascular endothelial growth factor expression by insulin-like growth factor I. R S Punglia , M Lu , J Hsu , M Kuroki , M J Tolentino , K Keough , A P Levy , N S Levy , M A Goldberg , R J D'Amato and A P Adamis Laboratory for Surgical Research, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Abstract Insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF) levels are correlated with retinal ischemia-associated intraocular neovascularization in humans. Since VEGF is required for iris and retinal neovascularization in animal models of retinal ischemia, we tested whether IGF-I could act as an indirect angiogenic factor by increasing VEGF gene expression. IGF-I increased retinal pigment epithelial (RPE) cell VEGF mRNA in a concentration-dependent manner with an EC50 of 7 nmol/1 (53.6 ng/ml). RPE and bovine smooth muscle cells exposed to 50 nmol/l (383 ng/m1) IGF-I achieved peak VEGF mRNA expression within 2 h. IGF-I-treated RPE cells increased VEGF protein levels in conditioned media and stimulated capillary endothelial cell proliferation. Blockade of the IGF-I receptor with a neutralizing antibody abrogated the VEGF increases in RPE cells. Further, hypoxia-mediated and IGF-I-mediated increases in VEGF mRNA and protein levels were additive in RPE cells, and the hypoxia-induced VEGF increases were independent of endogenous IGF-I. VEGF promoter activity was enhanced by IGF-I in RPE cells, but VEGF transcript half-life was unaltered. In summary, the supplementation of RPE and smooth muscle cell cultures with IGF-I at 5-100 nmol/l increased VEGF mRNA and secreted protein levels. The VEGF increases in RPE cells occurred primarily through enhanced transcription of the VEGF gene and via the IGF-I receptor. Elevated IGF-I levels may promote neovascularization through increased retinal VEGF gene expression.