ADHESION AND DIFFERENTIATION OF ENDOTHELIAL-CELLS BY EXPOSURE TO CHRONIC SHEAR-STRESS - A VASCULAR GRAFT MODEL

Long-term patency of artificial vascular grafts for hemodialysis access and for bypass or interposition in small caliber arteries is limited due to neointimal hyperplasia and associated graft thrombosis. Given the anticoagulant and vasodilatory properties of endothelial cells, these problems could be partially overcome if grafts were seeded with an adherent monolayer of differentiated endothelial cells, prior to implantation. Endothelial cells in vivo are highly adherent and can resist disruption by hemodynamic shear stress at levels that far exceed physiological conditions. Endothelial cells in vivo also are highly differentiated, with an organized cytoskeleton, Weibel-Palade bodies, and basal stress fibers with focal adhesion plaques. In cell culture, endothelial cells rapidly lose many of their differentiated features, and endothelial cells on artificial surfaces, like vascular graft material, are not sufficiently adherent or differentiated to resist physiologic shear stress. We find that endothelial cells exposed to chronic shear stress in vitro, applied in a stepwise fashion over several days, are induced to become tightly adherent to the substratum and exhibit more differentiated features. Thus, pre-conditioning of endothelial cells seeded on vascular grafts with stepwise shear stress in vitro could be used to improve endothelial cell retention and differentiation for subsequent in vivo use.