1,25-Dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGF promoter

Abstract

In previous studies we have demonstrated that the active form of vitamin D (1,25(OH)2D3) increases vascular endothelial growth factor (VEGF) expression and release in vascular smooth muscle cells (VSMC) in vitro. However, the mechanism by which 1,25(OH)2D3 increases VEGF production is currently unknown. In this work, we demonstrated binding of vitamin D receptor to two response elements in the VEGF promoter. We performed promoter transactivation analysis and we observed that, in 293T cells, VEGF promoter was activated after vitamin D treatment. Using site-directed mutagenesis we have shown that both response elements are important for VEGF promoter activity. Therefore, the increase in VEGF expression and secretion induced by 1,25(OH)2D3 in VSMC in vitro could be explained by direct binding of the vitamin D receptor, as a transcription factor, to VEGF promoter. These results could explain part of the beneficial effects of vitamin D treatment in renal patients by a possible VEGF-mediated improvement of the endothelial dysfunction.

This work was partially supported by grants from Fondo de Investigaciones Sanitarias (PI060010 and PI07/0427). The RETICS REDinREN (16/06) receives financial support from ISCIII. Jose M. Valdivielso and Xavier Dolcet hold a contract from FIS. Mario Encinas holds a contract from the Ramon y Cajal program. Sara Panizo holds a predoctoral fellowship from Generalitat de Catalu˜na (FI).