It appears that there are two classes of human circulating endothelial cell (EC) progenitors, CD34⁺ and CD34-CD14⁺ cells. Attention has focused on CD34⁺ cells, yet CD34^-CD14⁺ monocytic cells are far more abundant and may represent the most common class of circulating EC progenitor. Little is known about molecular or physiological factors that regulate putative CD34^-CD14⁺ EC progenitor function, though factors secreted by other blood and cardiovascular cells to which they are exposed probably affect their behavior. Hypoxia and stretch are two important physiological stimuli known to trigger growth factors in cardiovascular cells and accordingly may modulate EC progenitors. To investigate the impact of these environmental parameters on EC progenitors, EC production in CD34^-CD14⁺ cultures was evaluated. Our data indicate that neither stretch nor hypoxia alters EC production by EC progenitors directly, but do so indirectly through their effects on cardiovascular cells. Conditioned media (CM) from coronary artery smooth muscle cells inhibits EC production in culture, and this inhibition is stronger if the coronary smooth muscle cells have been subjected to cyclic stretch. In contrast, cardiomyocyte CM increases EC cell number, an effect that is potentiated if the myocytes have been subjected to hypoxia. Significantly, EC progenitor responses to CM are altered by the presence of CD34^-CD14^- peripheral blood mononuclear cells (PBMCs). Moreover, CD34^-CD14^-PBMCs attenuate EC progenitor responsiveness to the angiogenic factors FGF-2, VEGF-A₁₆₅, and erythropoietin while inducing EC progenitor death in the presence of TGF-₁ in vitro.