HEMODYNAMIC MODULATION OF MONOCYTIC CELL ADHERENCE TO VASCULAR ENDOTHELIUM

Hemodynamic shear stress is hypothesized to contribute to the localiza tion of atherosclerotic plaques to certain arterial sites. Monocyte re cruitment to these sites is an early event in atherogenesis. To determ ine the possible mechanisms by which shear stress modulates monocyte a dhesion in vivo, studies of human monocytic cell adherence to endothel ium were conducted under different shear conditions in a parallel-plat e flow chamber. The number of monocytes capable of developing firm adh esive contacts with endothelium decreased as shear stress-induced drag forces increased over the range of 0.5 to 30 dynes/cm(2). The number of adherent monocytic cells at a given shear stress was highly depende nt on the activation state of the endothelium. To test the direct effe ct of shear stress on endothelial cell adhesivity, endothelial cells w ere presheared for 2 to 6 hr at 2, 10, or 30 dynes/cm(2), and monocyti c cell adherence was quantified at 1 dyne/cm(2). Adherence increased 3 30% or 370% when endothelial cells were presheared for 2 hr at 2 or 10 dynes/cm(2), respectively, as compared to unsheared endothelium. In c ontrast, when endothelial cells were presheared at 30 dynes/cm(2), mon ocytic cell adherence at 1 dyne/cm(2) was not significantly different from unsheared controls. Increased monocytic cell adherence to preshea red endothelium was via a vascular cell adhesion molecule 1 (VCAM-1)/a lpha(4) beta(1) mechanism, and enzyme-linked immunosorbent assay studi es showed that preshearing at 2 dynes/cm(2) for 2 hr increased endothe lial VCAM-1 expression by 38%. These data demonstrate that low levels of shear stress induce endothelial VCAM-1 expression and increase mono cytic cell adherence via a VCAM-1/alpha(4) beta(1) mechanism. Thus, sh ear stress can modulate monocyte adherence to vascular endothelium thr ough drag forces that affect the establishment and maintenance of adhe sive bonds and by directly modulating the expression of endothelial VC AM-1. This dual effect of shear stress produces the most favorable con ditions for adhesion at low-shear regions, where drag forces are low a nd induction of VCAM-1 is likely. The preferential adherence of monocy tes to these regions may contribute to the localization of atheroscler otic plaques to low-shear regions of the arterial circulation in vivo.