Mechanisms regulating arteriolar vasomotor responses are numerous. However, the integrative process that results in a final response remains poorly understood. Much has been learned about the vasculature over the past hundred years by evaluating microcirculatory preparations in-situ with intravital microscopy, or by studying isolated segments of arterioles in-vitro, yet little is known about how all the different factors combine to make the final response. Dr. Rivers has developed a series of in-situ experiments to address this important aspect of integrated microvascular function. He proposes to study integrated arteriolar responses with a series of novel experiments that explore conducted vasomotion as a mechanism of integration. Recent work from his laboratory has revealed that vasomotor responses induced by changes in pressure and flow within an arteriole are communicated to other parts of the vasculature. Electrotonic communication, or conducted vasomotor responses, have been characterized as dilations or constrictions moving way from a site of drug stimulation, through gap junction communication in the vascular wail. Although much has been written about these conducted responses, this is the first demonstration that that cell-cell communication, previously demonstrated only through the activation of arterioles with drugs, may well play a physiological role in the coordination and regulation of blood flow. Physiological stimuli may use this pathway to communicate within the vasculature. The fundamental hypothesis is that conducted vasomotion integrates the component responses seen during the autoregulation of blood flow. Although the cell types and intracellular mechanisms are undefined, the phenomena is known to be consistent with cable properties having an exponential decay, and to have additive properties along the vessel wall. This grant proposes to determine four things l) the contributions of flow and pressure in conveying conducted responses, 2) the time and space limitation of the conducted response, 3) the contribution of conducted responses in reactive hyperemia, and 4) the intercellular and intracellular mechanisms involved in transducing electrotonic conduction into a vasomotor response. The four specific aims will be completed using video microscopy to measure the diameter responses of hamster cheek pouch arterioles in-situ in response to changes in pressure and flow within an isolated segment of arteriole. The segment will be isolated with two pairs of concentric pipettes that will cannulate and occlude the arteriole at two locations and allow control of pressure and flow between the pipette pairs. Cannulation and perfusion will take place without severing the arteriole from its native site. The isolated segment reacts normally to drugs, pressure, and flow; with conducted responses moving away from the isolated segment following the stimulation. By independently controlling perfusate, pressure, and flow within an isolated in-situ segment, the mechanisms and contributions of conducted vasomotion in integrating arteriolar responses can be determined. Dr. Rivers plans to first define the physiological and experimental limitations of the conducted response and then to treat the isolated segment in an effort to define the intracellular mechanisms. Understanding the processes involved in integrating the mechanisms of arteriolar responses will improve our ability to diagnose and treat vascular disorders such as hypertension and DIC, and vasospasm.
