1,25-dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGF promoter.
In previous studies we have demonstrated that the active form of vitamin D (1,25(OH)(2)D(3)) 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)(2)D(3) 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)(2)D(3) 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.
Cardus
Anna
A
Laboratorio de Investigación, Hospital Universitario Arnau de Vilanova, IRBLLEIDA, Spain. anna.cardus@medicina.udl.es
Panizo
Sara
S
Encinas
Mario
M
Dolcet
Xavier
X
Gallego
Carme
C
Aldea
Martí
M
Fernandez
Elvira
E
Valdivielso
Jose M
JM
D001483:Base Sequence; D002117:Calcitriol / Q000378:metabolism*; D002460:Cell Line; D017930:Genes, Reporter; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D018167:Receptors, Calcitriol; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D002117:Calcitriol