Nitric oxide synthase expression and functional response to nitric oxide are both important modulators of circulating angiogenic cell response to angiogenic stimuli.
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.
Heiss
Christian
C
Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143-0124, USA.
Schanz
Andrea
A
Amabile
Nicolas
N
Jahn
Sarah
S
Chen
Qiumei
Q
Wong
Maelene L
ML
Rassaf
Tienush
T
Heinen
Yvonne
Y
Cortese-Krott
Miriam
M
Grossman
William
W
Yeghiazarians
Yerem
Y
Springer
Matthew L
ML
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*
D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase