Local control mechanism(s) maintaining barrier function and modulating solute and fluid transport appear selective for specific vascular beds and microvessels. This specificity must be determined by the biology of the cells in the vascular walls, particularly the endothelial cell. Thus, these studies are described to continue our comparative investigation of microvascular structure and function in the cheek pouch of the hamster and in an inaccessible tissue, the human retina, using the hamster cheek pouch as a site for grafting. The central hypothesis is that control mechanisms are unique for each vascular bed and are mediated by structural and functional properties of the cells in the microvascular wall. Also, local regulation of transvascular exchange for water and large solutes in normal and activated states depends upon the initial state of the endothelial cells and/or other mural cells in the microvascular wall. The preset of initial conditions are complex and variable but their level of activity determines the duration and magnitude of the response by different agonists. As in other types of contractile cells, the level of stretch and/or degree of flow across the cell surface and the active state of intracellular transductor systems, e.g. calcium, inositol phosphate, protein kinase C, contribute to the basal and activated state for transvascular exchange. Further, the modulation of this exchange process has a final common pathway, re- organization of the cytoskeleton. Accordingly, these studies are designed to focus investigations into the cellular regulation and stabilization of the barrier function in microvessels of the mammal in normal states and after acute modification by inflammatory mediators without the complicating effect of circulating blood cells. Therefore, the specific aims are described as follows: 1. To determine the different cellular and/or transcellular pathways by which bradykinin (BK) and recombinant tumor necrosis factor alpha (rTNFalpha) alter the solute and water flux in microvessels. 2. To establish the relation between basal/activated water and macromolecular fluxes and: a) the degree of microvascular segment stretch/tension; and b) rate of volume flow through the exchange vessels. 3. To elucidate the different endothelial/mural cellular transduction mechanisms involved in the regulation of macromolecular fluxes in response to BK and rTNFalpha. 4. To examine, in situ, the role of cytoskeletal elements (actin) of endothelium and pericytes as the final common pathway in the regulation of microvascular solute exchange. 5. To analyze and compare the dependence of regulation of microvascular permeability on the specificity and homogeneity of the cells in the microvascular wall using the retinal graft. These studies will bridge the gap between information obtained from cells in culture with that obtained from whole organ studies and add pertinently to areas of inflammation and ischemia-reperfusion injury. Basic and new information concerning the cellular biology for control of microvascular dynamics will be obtained and, hopefully, provide new insights into these biological processes.
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