title: Modulation of neointimal lesion formation by endogenous androgens is independent of vascular androgen receptor.
abstract: OBJECTIVE
  Low androgen levels have been linked with an increased risk of cardiovascular disease in men. Previous studies have suggested that androgens directly inhibit atherosclerotic lesion formation although the underlying mechanisms for this remain unclear. This study addressed the hypothesis that endogenous androgens inhibit arterial remodelling by a direct action on the androgen receptor (AR) in the vascular wall.
  
  
  RESULTS
  We studied a series of novel mouse lines with cell-specific deletion of the AR in either the endothelium or in smooth muscle cells or both cell types. Findings were compared with a model of global androgen deficiency in wild-type mice (castrated). We characterized the cardiovascular phenotype, vascular pharmacology and histology, and assessed neointimal lesion formation following vascular injury to the femoral artery. Cell-specific AR deletion did not alter body weight, circulating testosterone levels or seminal vesicle weight, but caused limited alterations in arterial contractility and blood pressure. Neointimal lesion formation was unaltered by selective deletion of AR from the vascular endothelium, smooth muscle, or both cell types. Castration in wild-type mice increased neointimal lesion volume (Sham vs. Castration: 2.4 × 10(7) ± 4.5 × 10(6) vs. 3.9 × 10(7) ± 4.9 × 10(6) µm(3), P = 0.04, n = 9-10).
  
  
  CONCLUSIONS
  Vascular cell-specific AR deletion had no effect on neointimal lesion formation, while low systemic androgen levels adversely affect neointimal lesion size. These findings suggest that the cardio-protective effects of androgens are mediated either by AR outside the vasculature or by AR-independent mechanisms.
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Junxi
authors.initials: J
authors.lastname: Wu
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Iris
authors.initials: I
authors.lastname: Mair
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Win Gel
authors.initials: WG
authors.lastname: Lim
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Eileen
authors.initials: E
authors.lastname: Miller
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Denvir
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK lee.smith@ed.ac.uk.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Smith
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D058426:Neointima / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D057772:Vascular System Injuries / Q000378:metabolism*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen
keywords: Androgen receptor; Arterial injury; Neointima; Testosterone