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The nuclear receptor NOR‐1/NR4A3 regulates the multifunctional glycoprotein vitronectin in human vascular smooth muscle cells
Author(s) -
MartíPàmies Ingrid,
Cañes Laia,
Alonso Judith,
Rodríguez Cristina,
MartínezGonzález José
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700136rr
Subject(s) - vitronectin , vascular smooth muscle , chromatin immunoprecipitation , microbiology and biotechnology , biology , extracellular matrix , receptor , promoter , gene expression , gene , endocrinology , fibronectin , biochemistry , smooth muscle
The nuclear receptor NOR‐1 (NR4A3) has recently been involved in the regulation of extracellular matrix (ECM) proteins associated with neointimal thickening and the vascular control of hemostasis. We sought to find as‐yet unidentified NOR‐1 target genes in human vascular smooth muscle cells (VSMCs). An in silico analysis identified putative NOR‐1 response elements in the proximal promoter region of several genes encoding for ECM proteins, including vitronectin (VTN). Lentiviral overexpression of NOR‐1 strongly increased VTN mRNA and protein levels, whereas NOR‐1 silencing significantly reduced VTN expression. Deletion and site‐directed mutagenesis studies, as well as EMSA and chromatin immunoprecipitation, identified the NBRE(−202/−195) site in the VTN promoter as an essential element for NOR‐1 responsiveness. Furthermore, NOR‐1 and VTN colocalized in VSMCs in human atherosclerotic lesions. VTN levels were increased in cell supernatants from VSMCs that overexpress NOR‐1. Cell supernatants from VSMCs overexpressing NOR‐1 induced cell migration to a greater extent than supernatants from control cells, and this effect was attenuated when cell supernatants were preincubated with anti‐VTN blocking antibodies or VTN was silenced in supernatant‐generating cells. These results indicate that VTN is a target of NOR‐1 and suggest that this multifunctional glycoprotein may participate in vascular responses mediated by this nuclear receptor.—Martí‐Pàmies, I., Cañes, L., Alonso, J., Rodríguez, C., Martínez‐González, J. The nuclear receptor NOR‐1/NR4A3 regulates the multifunctional glycoprotein vitronectin in human vascular smooth muscle cells. FASEB J. 31, 4588–4599 (2017). www.fasebj.org