Go With the Flow

Physiologists have long recognized that blood vessels vasodilate in response to an increase of flow through their lumen.1 This flow-mediated vasodilation is not due to changes in luminal pressure, but rather to the tractive force of fluid flow, or shear stress.2 3 4 The endothelium senses shear stress by means of a mechanotransducer apparatus that is not fully defined but that may involve cytoskeletal deformation, activation of intracellular signaling molecules (such as the Smad proteins, mitogen-activated protein kinases, G proteins, and endothelial ion channels), and/or the release of endothelial agonists such as bradykinin.5 6 7 8 The endothelial mechanotransducer links the stimulus of flow to a response: vasodilation. This response results from the release of endothelial factors such as prostacyclin, endothelium-derived hyperpolarizing factor, and nitric oxide (NO).9 10 11 The latter has received much attention lately because it seems to be of primary importance in the flow-mediated vasodilation of most conduit vessels, most notably the human brachial artery.12 Flow-mediated vasodilation in the brachial artery is relatively simple to induce and easy to observe by duplex ultrasonography. Studies of flow-mediated vasodilation in the brachial artery have provided many insights into human endothelial physiology, including the adverse effects of risk factors on endothelial vasodilator function and the benefits of various interventions.13 14 The flow-stimulated release of endothelium-derived NO plays a critical role in the response to exercise. During exercise, the delivery of nutrients and oxygen to metabolically active skeletal muscle is critically dependent on flow-mediated vasodilation. When the NO synthase (NOS) pathway is impaired, either by hypercholesterolemia or by the administration of exogenous NOS antagonists, exercise-induced redistribution of blood flow to skeletal muscle is attenuated and exercise capacity is impaired.15 16 Specifically, in normal mice during peak exertion, the portion of the cardiac output that …