The long-term goal of this project is to define the cellular and molecular mechanisms that govern the integration and coordination of blood flow control. Electrical and vasomotor responses are conducted rapidly along arterioles and feed arteries to coordinate vasodilation and vasoconstriction in resistance networks. The working hypothesis is that conduction reflects the transmission of hyperpolarization (dilation) or depolarization (constriction) through gap junctions between endothelial cells (EC) and between smooth muscle cells (SMC) that comprise the vessel wall. The role of EC and SMC layers in conduction is unclear, as is the nature of coupling between respective layers. Further, conduction varies between microvessels of the epithelial hamster cheek pouch and its contiguous retractor (skeletal) muscle. The basis of these regional differences may be associated with corresponding differences in sympathetic innervation and/or gap junction expression within and between cell layers. Arterioles and feed arteries from cheek pouch and retractor will be studied in vivo and in vitro.
The specific aims are to determine: 1) the role of EC and SMC as conduction pathways; 2) the nature of coupling between EC and SMC layers; and 3) the influence of sympathetic innervation and gap junction expression on conducted vasomotor responses. Micropipettes deliver stimuli that act selectively on SMC or on EC, and intracellular recording with dye labeling resolves SMC and EC specific signaling events. Selective disruption of EC or SMC signaling is achieved through light dye damage and pharmacological intervention. The results will define the roles of EC and SMC layers as signaling pathways, define the nature (chemical and/or electrical) of communication between EC and SMC layers, and will link the determinants of conduction with regional differences in innervation and gap junction expression. These findings will provide insight into how the control of microvascular resistance may vary between tissues that differ in structure and function. In addition, distinguishing the roles of SMC and EC in the initiation and conduction of vasomotor responses in vessels that control blood flow to epithelium and skeletal muscle will contribute to the understanding of how tissue perfusion is compromised in conditions such as atherosclerosis, diabetes, hypertension, and ischemia.
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