THE EFFECT OF STEADY AND OSCILLATORY SHEAR STRESS ON ENDOTHELIAL CELL FUNCTION
FRANGOS, JOHN ANDREOU
Doctor of Philosophy
It has become increasingly evident that hemodynamic shear stresses have an important role in both the normal physiology and the pathobiology of the vascular endothelium. In this study, the effects of physiological levels of shear stress on the functional response of primary human umbilical vein endothelial cells were investigated. Two functional properties that are of primary importance to endothelial cells were chosen for study: the production of prostacyclin, a potent anti-platelet agent and vasodilator; and the assembly and release of von Willebrand factor, which is important in platelet-platelet and platelet-subendothelial interactions. To stimulate the hemodynamic environment of the circulation and to examine the effect of both steady and pulsatile shear stresses on the endothelium, a flow apparatus to subject cultured cells to well-characterized shear was developed. The onset of shear led to a sudden increase in the production of prostacyclin which decreased to a constant or steady state rate within several minutes. The steady state production rate was a function of the magnitude of shear, and varied linearly in the range of shears we studied. The steady state production rate was also a function of the unsteadiness of the fluid shear. Pulsatile shear stress stimulated prostacyclin production even more than steady shear stress. In addition, the shear stress-induced steady state production rate was at least partially dependent on the presence of exogeneous substrate, arachidonic acid. Our prostacyclin studies provide further evidence that the qualitative nature of blood flow may have a controlling role in endothelial cell function. During the course of our investigation of the effects of shear stress on the release of von Willebrand factor, we have found an activity in normal plasma that processes the unusually large von Willebrand multimers to somewhat smaller plasma vWF forms.