The Erythrocyte: a Regulator of Microvascular Perfusion

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DESCRIPTION (provided by applicant): The goal of this project is to substantiate a role for the red blood cell (RBC) in the control of perfusion of the peripheral microcirculation. The precise matching of oxygen (02) supply to demand requires a sensor of tissue 02 need and affector of alterations in 02 supply to meet those needs. Our earlier studies indicated RBC 02 content is more important in maintaining tissue 02 supply than is its P02 when 02 supply is limiting. Since the only portion of the 02 transport pathway directly influenced by 02 content is the hemoglobin within the RBC we suggest that the RBC is involved in both sensing 02 demand and regulating blood flow in response to local 02 need.The 02 content of the RBC at a particular point in the tissue is directly linked to the level of oxygen use by the tissue. If the mobile RBC itself were able to sense 02, need and modulate vascular calibre, blood flow and 02 delivery would be increased wherever and whenever the need might arise thereby eliminating the need for diverse network of sensing sites throughout the vasculature. ATP is released from RBCs in response to low P02 and when applied intraluminally into arterioles and venules induces a conducted vasodilator response. These results led us to formulate the hypothesis that: the red blood cell, in addition to serving as the primary carriei of oxygen, is a sensor of tissue oxygen requirements and initiator of a conducted vasodilator response via its release of ATP which enables the appropriate matching of oxygen supply with demand.Four approaches will be used to evaluate this hypothesis: 1) Using isolated hamster retractor muscle arteriole and venules, we will ascertain the nature of the purinergic receptors located on these vessels; 2) Since we have shown that elevated lactate impairs the ability of the RBC to release ATP, we will determine if this deficit has an impact on vascular control, studies which will provide insight into derangements in tissue 02 supply observed ii malaria, sepsis and other pathological conditions; 3) Using the retractor muscle in situ, we will confirm the relationship among low P02, RBC-induced ATP release and vasodilation in vivo; 4) We will determine how decreases in hemoglobin 02 saturation activate the signal transduction pathway for ATP release. These findings will be combined into a physiological model for the regulation of blood flow distribution to meet tissue needs and may provide insight into the impairment in peripheral oxygenation observed frequently in pathological conditions.