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P. C. Kothary, P. Lee, M. A. Del Monte; Effect of Insulin Like Growth Factor-1 on Vascular Endothelial Growth Factor Receptor-2 in Human Retinal Pigment Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5955.
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Vascular endothelial growth factor (VEGF) and the human retinal pigment epithelium (hRPE) have been implicated in proliferative eye diseases and diabetic retinopathy. Since abnormal expression of insulin like growth factor-1 (IGF-1) has been demonstrated in patients with diabetic eye complications, we have investigated the effect of IGF-1 on intracellular synthesis of VEGF-R2, one of two known VEGF receptors, and possible mechanisms for any pathological interaction.
hRPE cell cultures were established from human eyes from the Michigan Eye Bank. hRPE cell viability was determined by the trypan blue exclusion method (T) and by measuring thymidine incorporation (3H-thy). 14C-methionine-VEGFR2 (14C-VEGFR2) production was measured by immunoprecipitation. Production of VEGF-R2 in hRPE cells was examined by immunohistostochemistry. Cells were also treated with PD98059(PD), a selective small molecule inhibitor of mitogen activated protein kinase (MAPK). Data were analyzed by Student 't' test.
hRPE cell proliferation was stimulated by IGF-1 in a dose dependant manner as determined by 3H-thy and T. PD significantly inhibited IGF-1 stimulated proliferation as determined by 3H-thy incorporation, (998.5±186.70 vs. 1328.75±213.88, CPM±SEM, p<0.05,N=4). IGF-1 also stimulated immuno-precipitated 14C-VEGFR2 in a dose dependant manner and this stimulation was also inhibited by PD, (1044.86±754.93 vs. 2868.29±600.35, CPM±SEM, p<0.05,N=6). Immuno-histochemistry demonstrated more VEGF-R2 positive immuno-reactive hRPE cells in presence IGF-1 than in control and IGF-1+PD treated cells.
These data suggest that the mitogen activated protein kinase pathway (MAPK) may play a role in IGF-1 stimulated intracellular synthesis of VEGF - R2. This interaction may provide additional options for the development of pharmacologic agents to treat or prevent proliferative vitreo-retinopathy in diabetes and other pathologic retinal disorders.
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