title: The androgen receptor drives the sex-specific expression of vascular cell adhesion molecule-1 in endothelial cells but not lipid metabolism genes in monocyte-derived macrophages.
abstract: BACKGROUND
  Anecdotal evidence suggests that male sex hormones are proatherogenic. We hypothesized that the male sex hormone receptor, the androgen receptor (AR), acts as a molecular switch in sex-specific inflammatory signaling in vascular cells.
  
  
  METHODS
  AR expression in human umbilical vein endothelial cells (HUVECs), human monocyte-derived macrophages (MDMs) or HeLa cells was modulated by transfection with AR siRNA or human AR cDNA expression vector. Activity and expression levels were measured by luciferase reporter assays, Western blotting or real-time PCR analysis.
  
  
  RESULTS
  AR knockdown reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in genetically male HUVECs. Conversely, AR upregulation in genetically female HUVECs induced VCAM-1 expression and increased dihydrotestosterone-stimulated monocyte adhesion. Co-transfection of an AR expression vector with VCAM-1 or NF-κB-reporter vectors into phenotypically female, AR-negative HeLa cells confirmed AR regulation of VCAM-1 expression as well as AR activation of NF-κB. AR upregulation was not sufficient to increase ICAM-1 levels in female HUVECs or lipoprotein metabolism gene expression in female MDMs, despite AR knockdown limiting expression in their male counterparts.
  
  
  CONCLUSIONS
  AR acts as a molecular switch to induce VCAM-1 expression. Low AR levels in female HUVECs limit NF-κB/VCAM-1 induction and monocyte adhesion and could contribute to the gender bias in cardiovascular disease. Unidentified factors in female cells limit induction of other proatherogenic genes not primarily regulated by NF-κB.
authors.forename: Kristine C-Y
authors.initials: KC
authors.lastname: McGrath
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Hill
authors.forename: Lucinda S
authors.initials: LS
authors.lastname: McRobb
authors.forename: Alison K
authors.initials: AK
authors.lastname: Heather