title: OS075. Endothelial-dependent vascular function is significantly impaired in obesity and restored by overexpression of DDAH1: Evidence for the role of ADMA.
abstract: BACKGROUND
  Obesity is a significant independent risk factor for preeclampsia. Vascular dysfunction is a central pathophysiological feature of preeclampsia. Vascular dysfunction is common in obesity. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and metabolized primarily by the enzyme DDAH1. ADMA is significantly elevated in obesity and preeclampsia.
  
  
  OBJECTIVE
  The focus of this study was to investigate the role of elevated ADMA in obesity-mediated vascular dysfunction.
  
  
  METHODS
  Endothelial-dependent and independent- vascular function of mesenteric arteries was assessed using an isometric myograph. Arteries from pregnant female C57/B6J control lean (n=7), control obese (n=12), DDAH1 overexpressing lean (n=6) and DDAH1 obese (n=10) mice were investigated. Obesity was induced by a high fat diet (42% fat, with adjusted calories, Harlan Teklad) for 8 weeks prior to mating. Data were analyzed by repeated measures ANOVA with significance at p<0.05.
  
  
  RESULTS
  DDAH1 transgenic mice and control wild-type mice both increased body weight significantly on the high fat diet compared to lean mice (p<0.01). Obese mice also evidenced significantly elevated leptin concentrations (control obese= 4.1ng/ml and DDAH1 obese 3.9ng/ml) compared to lean mice (1.1ng/ml, p<0.05) reflecting increased adiposity. Contractile response to phenylephrine was not different between arteries from all groups of pregnant mice, however tension was greater in arteries from control obese mice compared to control lean mice (p<0.01). Methacholine-induced endothelial-dependent relaxation was significantly blunted in arteries from control obese mice (66±14%) compared to control lean mice (93±2%, p<0.001). In contrast, endothelial-dependent relaxation was intact in arteries from DDAH1 obese mice (90±8%). Endothelial-dependent relaxation was restored in arteries from control obese mice by ex-vivo incubation with L-arginine (91±9%). Endothelial-dependent relaxation was not different between arteries from all groups of mice in the presence of the nitric oxide synthase inhibitor L-NAME. Similarly, endothelial-independent relaxation in response to nitroprusside was not different between arteries from all groups of mice.
  
  
  CONCLUSIONS
  Overexpression of the ADMA metabolizing enzyme DDAH1 is protective of the obesity-mediated loss in endothelial-dependent relaxation. These data suggest that elevated ADMA is a significant contributor to vascular dysfunction in pregnancy.
  This project supported by National Institutes of Health grant R01-HL091094.
authors.affiliation: Ob & Gyn, University of Pittsburgh, Pittsburgh, United States.
authors.forename: R
authors.initials: R
authors.lastname: Powers
authors.affiliation: Ob & Gyn, University of Pittsburgh, Pittsburgh, United States.
authors.forename: J
authors.initials: J
authors.lastname: Gefter