title: Impaired Vitamin D Signaling in Endothelial Cell Leads to an Enhanced Leukocyte-Endothelium Interplay: Implications for Atherosclerosis Development.
abstract: Endothelial cell activation leading to leukocyte recruitment and adhesion plays an essential role in the initiation and progression of atherosclerosis. Vitamin D has cardioprotective actions, while its deficiency is a risk factor for the progression of cardiovascular damage. Our aim was to assess the role of basal levels of vitamin D receptor (VDR) on the early leukocyte recruitment and related endothelial cell-adhesion-molecule expression, as essential prerequisites for the onset of atherosclerosis. Knockdown of VDR in endothelial cells (shVDR) led to endothelial cell activation, characterized by upregulation of VCAM-1, ICAM-1 and IL-6, decreased peripheral blood mononuclear cell (PBMC) rolling velocity and increased PBMC rolling flux and adhesion to the endothelium. shVDR cells showed decreased IκBα levels and accumulation of p65 in the nucleus compared to shRNA controls. Inhibition of NF-κB activation with super-repressor IκBα blunted all signs of endothelial cell activation caused by downregulation of VDR in endothelial cells. In vivo, deletion of VDR led to significantly larger aortic arch and aortic root lesions in apoE-/- mice, with higher macrophage content. apoE-/-VDR-/-mice showed higher aortic expression of VCAM-1, ICAM-1 and IL-6 when compared to apoE-/-VDR+/+ mice. Our data demonstrate that lack of VDR signaling in endothelial cells leads to a state of endothelial activation with increased leukocyte-endothelial cell interactions that may contribute to the more severe plaque accumulation observed in apoE-/-VDR-/- mice. The results reveal an important role for basal levels of endothelial VDR in limiting endothelial cell inflammation and atherosclerosis.
authors: Nephrology Research Department, IRB Lleida, Lleida, Spain.
authors: Milica
authors: M
authors: Bozic
authors: Department of Pharmacology and CIBERehd, University of Valencia, Valencia, Spain.
authors: Ángeles
authors: Á
authors: Álvarez
authors: Department of Pharmacology and CIBERehd, University of Valencia, Valencia, Spain.
authors: Carmen
authors: C
authors: de Pablo
authors: IIS-Fundacion Jimenez Diaz, School of Medicine, UAM and IRSIN, Madrid, Spain.
authors: Maria-Dolores
authors: MD
authors: Sanchez-Niño
authors: IIS-Fundacion Jimenez Diaz, School of Medicine, UAM and IRSIN, Madrid, Spain.
authors: Alberto
authors: A
authors: Ortiz
authors: Pathology Group, Pathology and Molecular Genetics Department, Hospital Universitari Arnau de Vilanova, University of Lleida and IRB Lleida, Spain.
authors: Xavier
authors: X
authors: Dolcet
authors: Department of Experimental Medicine, University of Lleida and IRB Lleida, Lleida, Spain.
authors: Mario
authors: M
authors: Encinas
authors: Nephrology Research Department, IRB Lleida, Lleida, Spain.
authors: Elvira
authors: E
authors: Fernandez
authors: Nephrology Research Department, IRB Lleida, Lleida, Spain.
authors: José Manuel
authors: JM
authors: Valdivielso
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism*; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D018167:Receptors, Calcitriol / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D018167:Receptors, Calcitriol; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D014807:Vitamin D