(Modified from the applicant): It is well established that nitric oxide (NO), is produced by endothelial cells and is capable of relaxing vascular smooth muscle. Alterations in shear stress have been suggested to be a major stimulus for NO release from the endothelium. A reappraisal of this viewpoint was required, however, when the investigators found that in the rabbit pulmonary circulation, in the absence of red blood cells (RBCs), alterations in shear stress alone did not evoke NO release. Therefore, it was concluded that, in the pulmonary circulation, an interaction, not related to shear stress, occurs between the RBC and the endothelium resulting in NO synthesis. In the present study it is hypothesized that the RBC releases a mediator that, in turn, stimulates NO synthesis, affecting, thereby, local hemodynamic changes. It is postulated that the mediator released is adenosine triphosphate (ATP) and that an important stimulus for the release of ATP is mechanical deformation of the RBC. In the present proposal the aims are to 1) characterize the contribution of the RBC and ATP to vascular caliber in the intact lung, 2) determine that mechanical deformation of the RBC is a stimulus for the release of ATP from that cell, 3) establish that RBC-derived ATP results in endothelial NO synthesis, 4) demonstrate that the mechanism by which ATP is released from the RBC in response to mechanical deformation is via the activity of the cystic fibrosis transmembrane conductance regulator and 5) establish that NO released into the vascular lumen alters RBC deformability leading to reduced ATP release. The thesis that mechanical deformation of RBCs leads to ATP release which, in turn, stimulates NO synthesis suggests a novel and important mechanism for the local control of vascular caliber. In this construct, the RBC is increasingly deformed by increments in blood flow through a vessel of constant or decreasing radius or by reductions in vascular caliber at constant or increasing flow. In response to deformation, ATP is released from the RBC which stimulates NO synthesis by endothelial cells. The abluminal release of NO results in relaxation of vascular smooth muscle leading, ultimately, to a decrease in the stimulus for RBC deformation, thereby, limiting the stimulus for ATP release and NO synthesis. In addition, NO released into the vascular lumen interacts with the RBC leading to increased deformablity and reduced ATP release, again limiting the stimulus for ATP release. This hypothesis is the logical progression of previous work and is consistent with a major focus of this group, namely identification and characterization of those mechanisms responsible for the control of vascular resistance.
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