In summary, our studies, utilizing the intact lung and several in vitro models, have shown a characteristic response of flow-adapted endothelial cells to ischemia. We believe that this effect represents a response to decreased shear stress since it is unrelated to cellular oxygenation. The response is characterized by endothelial cell depolarization, followed by activation of the membrane-bound NADPH oxidase with generation of ROS, cell signaling, activation of transcription factors, and increased cell division. We postulate that the physiologic role of this response is an attempt to restore blood flow through vasodilation and the repair or genesis of blood vessels.