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.

Methods and Results Similar to endothelial cells, CAC chemotaxis to VEGF was blocked by inhibition of NOS, phosphoinositide-3 kinase, or guanylyl cyclase, or by treatment with an NO scavenger. Addition of a NO donor (SNAP) and the NOS-substrate L-arginine increased random cell migration (chemokinesis) and enhanced VEGF-dependent chemotaxis. Healthy CACs expressed eNOS, but eNOS was not detected in CAD patient CACs. Both chemokinesis and chemotaxis to VEGF of patient CACs were decreased compared to healthy CACs, but were restored to healthy values by SNAP. 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 CAC dysfunction and limit their regenerative capacity.