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Flow: the signal of life.

See related article, pages 841–847 

Ever since the German physiologist Schretzenmayr1 at the beginning of the last century observed a widening of large arteries on exposure to increased flow, it was clear that blood vessels were not tubes, but able to react to forces exerted by the circulating blood. The sensor of flow was only discovered much later, when endothelial cells were recognized as a rich source of vasoactive mediators. At first the release of prostacyclin from cultured endothelial cells was shown to be shear stress dependent.2 The discovery of endothelium-dependent relaxations to acetylcholine in 1980 by Furchgott3 inspired a search for physiological stimuli for the putative endothelium-derived relaxing factor (EDRF). Indeed, in perfused femoral arteries of the dog, increases in flow markedly augmented the release of EDRF,4 a phenomenon that was soon confirmed in vivo as well.

The identification of EDRF as nitric oxide (NO)5 in 1987 and later the cloning of all three isoforms of the enzyme nitric oxide synthase (NOS) provided better tools to characterize the mediators of flow-dependent vasodilation. Inhibitors of NO such as N G-monomethyl-l-arginine (l-NMMA) and N G-nitro-l-arginine methyl ester (l-NAME) were able to prevent flow-mediated vasodilation in isolated arteries in animal models and in the human forearm.6 Thus, it became quite clear that shear stress exerted by the circulating blood elicits the release of NO from endothelial cells. Based on these findings, it was hypothesized that such a mechanism not only would provide higher vascular conductance (for instance in the coronary circulation under conditions of increased demand such as exercise), but also would ensure continued inactivation of circulating platelets in spite of the increased shear exerted on them.7 Furthermore, other protective effects of NO against the expression of …