title: Regulation of vascular endothelial growth factor expression by insulin-like growth factor I.
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.
authors.affiliation: Laboratory for Surgical Research, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Punglia
authors.forename: M
authors.initials: M
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Hsu
authors.forename: M
authors.initials: M
authors.lastname: Kuroki
authors.forename: M J
authors.initials: MJ
authors.lastname: Tolentino
authors.forename: K
authors.initials: K
authors.lastname: Keough
authors.forename: A P
authors.initials: AP
authors.lastname: Levy
authors.forename: N S
authors.initials: NS
authors.lastname: Levy
authors.forename: M A
authors.initials: MA
authors.lastname: Goldberg
authors.forename: R J
authors.initials: RJ
authors.lastname: D'Amato
authors.forename: A P
authors.initials: AP
authors.lastname: Adamis
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015152:Blotting, Northern; D002196:Capillaries; D002455:Cell Division; D015687:Cell Hypoxia; D002461:Cell Line, Transformed; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007700:Kinetics; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000906:Antibodies; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1