title: Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide.
abstract: BACKGROUND
  Nitric oxide ((•)NO) is more effective at inhibiting neointimal hyperplasia following arterial injury in male versus female rodents, though the etiology is unclear. Given that superoxide (O2(•-)) regulates cellular proliferation, and (•)NO regulates superoxide dismutase-1 (SOD-1) in the vasculature, we hypothesized that (•)NO differentially regulates SOD-1 based on sex.
  
  
  METHODS
  Male and female vascular smooth muscle cells (VSMC) were harvested from the aortae of Sprague-Dawley rats. O2(•-) levels were quantified by electron paramagnetic resonance (EPR) and HPLC. sod-1 gene expression was assayed by qPCR. SOD-1, SOD-2, and catalase protein levels were detected by Western blot. SOD-1 activity was measured via colorimetric assay. The rat carotid artery injury model was performed on Sprague-Dawley rats ±(•)NO treatment and SOD-1 protein levels were examined by Western blot.
  
  
  RESULTS
  In vitro, male VSMC have higher O2(•-) levels and lower SOD - 1 activity at baseline compared to female VSMC (P < 0.05). (•)NO decreased O2(•-) levels and increased SOD - 1 activity in male (P<0.05) but not female VSMC. (•)NO also increased sod- 1 gene expression and SOD - 1 protein levels in male (P<0.05) but not female VSMC. In vivo, SOD-1 levels were 3.7-fold higher in female versus male carotid arteries at baseline. After injury, SOD-1 levels decreased in both sexes, but (•)NO increased SOD-1 levels 3-fold above controls in males, but returned to baseline in females.
  
  
  CONCLUSIONS
  Our results provide evidence that regulation of the redox environment at baseline and following exposure to (•)NO is sex-dependent in the vasculature. These data suggest that sex-based differential redox regulation may be one mechanism by which (•)NO is more effective at inhibiting neointimal hyperplasia in male versus female rodents.
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, IL, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA.
authors.forename: Rommel C
authors.initials: RC
authors.lastname: Morales
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, IL, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA.
authors.forename: Edward S M
authors.initials: ES
authors.lastname: Bahnson
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, IL, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Havelka
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Nadiezhda
authors.initials: N
authors.lastname: Cantu-Medellin
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Kelley
authors.affiliation: Division of Vascular Surgery, Northwestern University, Chicago, IL, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA. Electronic address: mkibbe@nmh.org.
authors.forename: Melina R
authors.initials: MR
authors.lastname: Kibbe
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism
chemical_list: D020030:Nitric Oxide Donors; D013481:Superoxides; D009569:Nitric Oxide; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Neointimal hyperplasia; Nitric oxide; Sex differences; Superoxide; Vascular