We have developed a new computerized biomechanical ex vivo perfusion system for intact conduit vessels in which a wide range of combinations of intraluminal pressure, fluid flow and shear stress could be set and maintained at target levels in mammalian conduit vessels under controlled metabolic conditions. Mean wall shear stress is calculated using the formula:τ = 1/2 * (ΔP/L)<sup>3/4</sup> * (8ηQ/Π)<sup>1/4</sup>.Accuracy of the wall shear stress calculation was validated by ultrasonographic imaging of the vessel radius. In a series of simulation experiments, the hemodynamic homeostasis functions of the system were challenged by generating a wide range of vascular resistance in artificial vessels and by pharmacologically induced changes in vascular tone in intact human vessels. Despite rapid changes in vessel resistance, shear stress and pressure, or flow and pressure were maintained well at target levels. Shear- and pressure-stimulated production of the vasodilator prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) was used to validate the biological relevance of the model. PGE<sub>2</sub> release was significantly more stimulated by high (25 dyn/cm<sup>2</sup>) compared to low (<4 dyn/cm<sup>2</sup>) shear (ANOVA, p = 0.012). High compared to low intraluminal pressure depressed the production of PGE<sub>2</sub> (ANOVA, p = 0.019). In summary, the computerized perfusion model appears to offer new possibilities of investigating the complex interplay between fluid mechanics and the vascular wall.