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1 From the Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; and the 2 Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
PURPOSE. Angiotensin II (AII) has been shown to play a role in many vascular diseases. In the study described, the effect of AII on vascular endothelial growth factor (VEGF) expression and related intracellular signaling mechanism was investigated in bovine retinal microcapillary pericytes.
METHODS. Cultured bovine retinal microvascular endothelial cells and pericytes were prepared. VEGF expression was determined by Northern blot analysis and immunoprecipitation assay. Cell proliferation was assessed by DNA content growth assay. Reporter gene studies were performed to identify the AII responsible transcription-activating region of VEGF gene.
RESULTS. Angiotensin II induced a significant increase in VEGF mRNA in a time- and dose-dependent manner. Angiotensin II type I receptor antagonist inhibited this effect. Angiotensin II activates the transcription of VEGF gene without changing the mRNA half-life, and the AII responsible region was found in the 5'-flanking region of the VEGF gene. Angiotensin II also increased the expression of c–fos and c–jun mRNA, and antisense oligonucleotides against c-Fos blocked the AII–induced VEGF mRNA expression. The conditioned media of AII–stimulated pericyte cultures had a growth-promoting effect on endothelial cells, and this effect was inhibited almost completely by VEGF neutralizing antibody.
CONCLUSIONS. These findings suggest that AII might induce angiogenic activity through a paracrine function of VEGF in retinal microvascular cells.
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