title: Nitric oxide synthase expression and functional response to nitric oxide are both important modulators of circulating angiogenic cell response to angiogenic stimuli.
abstract: OBJECTIVE
  Circulating angiogenic cells (CACs), also termed endothelial progenitor cells, play an integral role in vascular repair and are functionally impaired in coronary artery disease (CAD). The role of nitric oxide (NO) in CAC function is poorly understood. We hypothesized that CAC migration toward angiogenic signals is modulated by both NO synthase (NOS) expression and functional response to NO.
  
  
  RESULTS
  Similar to endothelial cells, CAC chemotaxis to vascular endothelial growth factor (VEGF) was blocked by inhibition of NOS, phosphatidylinositol 3-kinase, or guanylyl cyclase or by treatment with an NO scavenger. Addition of an NO donor (S-nitroso-N-acetylpenicillamine) and the NOS substrate l-arginine increased random cell migration (chemokinesis) and enhanced VEGF-dependent chemotaxis. Healthy CACs expressed endothelial NOS, but endothelial NOS was not detected in CAD patient CACs. Both chemokinesis and chemotaxis to VEGF of patient CACs were decreased compared with healthy CACs but were restored to healthy values by S-nitroso-N-acetylpenicillamine. In parallel, CAD patients exhibited lower flow-mediated vasodilation and plasma NO source nitrite than young, healthy subjects, indicating endothelial dysfunction with reduced NO bioavailability.
  
  
  CONCLUSIONS
  NOS activity is required for CAC chemotaxis. In CAD patients, impairment of NOS expression and NO bioavailability, rather than response to NO, may contribute to dysfunction of CACs and limit their regenerative capacity.
authors: Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143-0124, USA.
authors: Christian
authors: C
authors: Heiss
authors: Andrea
authors: A
authors: Schanz
authors: Nicolas
authors: N
authors: Amabile
authors: Sarah
authors: S
authors: Jahn
authors: Qiumei
authors: Q
authors: Chen
authors: Maelene L
authors: ML
authors: Wong
authors: Tienush
authors: T
authors: Rassaf
authors: Yvonne
authors: Y
authors: Heinen
authors: Miriam
authors: M
authors: Cortese-Krott
authors: William
authors: W
authors: Grossman
authors: Yerem
authors: Y
authors: Yeghiazarians
authors: Matthew L
authors: ML
authors: Springer
mesh_terms: D002465:Cell Movement; D002633:Chemotaxis / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D013234:Stem Cells / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase