Vascular endothelial growth factor synthesis in vascular smooth muscle cells is enhanced by 7-ketocholesterol and lysophosphatidylcholine independently of their effect on nitric oxide generation

Abstract

Nitric oxide (NO) generated by inducible NO synthase (iNOS) enhances vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle cells (VSMC) and both NO and modified low density lipoprotein (LDL) augment VEGF production in macrophages. Oxidized LDL (oxLDL) are known inhibitors of NO generation in the cells of vascular wall. As the relationship between VEGF, iNOS and oxLDL has not been well elucidated, we studied the effect of two main components of oxLDL, 7-ketocholesterol (7-Kchol) and lysophosphatidylcholine (LPC), on VEGF and NO synthesis in rat VSMC and on VEGF synthesis in human VSMC. Both LPC and 7-Kchol significantly augmented VEGF production in rat and human VSMC. Increase in VEGF generation was related to the activation of VEGF promoter by both 7-Kchol and LPC and enhancement of VEGF mRNA transcription. In rat, VSMC IL-1β-induced NO generation and enhanced VEGF synthesis. 7-Kchol decreased rat iNOS promoter activity, iNOS expression and NO generation, but it did not impair IL-1β-induced VEGF synthesis. LPC did not significantly influence IL-1β-induced NO production in rat VSMC and VEGF synthesis was significantly enhanced by combined treatment with IL-1β and LPC in comparison to the effect of either compound alone. The results indicate that VEGF and NO synthesis in VSMC can be modulated by oxLDL. Those interactions might have an effect on the plaque growth and might be of relevance for the physiology of vascular wall cells.