Cell-cell signaling within the arteriolar wall provides a vital link uniting individual vascular smooth muscle and endothelial cells into a functional resistance vessel which can operate as a part of the microcirculation. Chemical signaling (e.g. EDRF), the myogenic mechanism, flow dependent dilation and the conducted vasomotor response are all involved. These processes serve not only to unify the activities of the individual cells, but also to coordinate the series and parallel elements of the vasculature so as to assure the uniform distribution of blood flow among and within the various organs The cellular and molecular bases of the conducted vasomotor response have been the least investigated of any of the integrative mechanisms, and our laboratory has undertaken a multidisciplinary program aimed at rectifying this deficit, and in providing insights into the basic physiology and pathophysiology of the vascular wall. Two broad questions are addressed. What are the cellular events leading to conduction, and what are the pathways involved in conduction? Our tools include: in vitro and in vivo whole-cell electrical recording from micropipettes in addition to voltage sensitive dyes for measurement of membrane potential of vascular smooth muscle and endothelial cells, calcium sensitive dyes to monitor Ca++ signaling, dye injection to trace cellular connectivity, immunohistochemistry to define the anatomical pathways of connectivity in the vessel wall, and in situ hybridization to determine the cells of origin for connexin proteins (gap junctions). We propose to use these tools in combination with cell and receptor specific agonists, gap junction uncouplers, and antisense oligonucleotides to test six critical hypotheses. l. A change in membrane potential is the necessary and the sufficient signal for conducted vasomotor response. 2. Longitudinal diffusion of Ca+ + or other second messenger contributes to longitudinal communication. 3. Either smooth muscle or endothelium may participate in a.) initiating, and b.) conducting the response. 4. The capillary endothelium is a conduction pathway uniting capillaries and arterioles. 5. The gap junctions provide both homocellular and heterocellular pathways for conduction. 6. The intercellular conduction system in the arteriolar wall is under physiological control.
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