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BBB seminar: Fitz-Roy E. Curry

Acute and chronic regulation of microvascular exchange at the endothelial barrier

Fitz-Roy E. Curry
Department of Physiology and Membrane Biology, School of Medicine, University of California, USA

The classical pore theory of capillary permeability describes water and water soluble solute exchanges across the microvessel wall in terms of viscous resistance within cylindrical pores of narrow slits within the junctions between adjacent endothelial cells. The physical and chemical nature of these porous pathways is still not well understood, but is best explained in terms a surface glycocalyx which forms the primary molecular sieve (determinant of pore size) in series with infrequent breaks in the junctional strands (determinant of pore number). I will discuss the regulation of water and solute exchange across microvascular endothelium in terms of the driving forces for water and solute transport across this series barrier and the mechanisms regulating acute and chronic changes in the structure of the glycocalyx and junction strands. For example, one prediction from the structure of the barrier is that the difference in plasma protein effective osmotic pressure (σΔπ) that opposes the hydrostatic pressure differences (ΔP) in the classical Starling Principle for fluid exchange is exerted mainly across the surface glycocalyx. I will discuss experiments to test this idea in individually perfused mammalian microvessels where junction ultrastructure is directly measured (J Physiol epub April 8, 2004) and evaluate the application of this concept to other microvascular beds. We and others have described changes in the glycocalyx leading to increased permeability that depend on the composition of the plasma proteins. Platts and Duling (Circ Research 92:77, 2004) describe decreased exclusion of macromolecules from the glycocalyx in arterioles after exposure to a number of agents and conditions including ischemia-reperfusion. I will also describe experiments to evaluate the balance between cell-cell adhesion and contractile forces, as well as actin organization, in endothelial cells to regulate microvessel permeability. The experiments indicate that the contribution of contractile mechanism to acute increases in permeability in intact microvessel is much less than in many cultured monolayers (Am J Physiol 285:H406, 2003). Furthermore, some of the mechanisms regulating cultured endothelial cell monolayer permeability are more representative of endothelial cells of intact microvessels 24 hours after exposure to mild injury than of endothelial cells in microvessels with no prior exposure to injury (Am J Physiol 285:H2446, 2003). These observations contribute to the evolving concept of the plasticity of endothelial cell phenotypes, particularly in response to injury.

Professor Fitz-Roy E. Curry is one of the leading pioneers in the field of microcirculation. His work consists of theoretical and experimental studies on the regulation of the transport of water and solutes across the walls of microvessels. His experimental approach involves the cannulation and perfusion of individual microvessels. Using this approach he can quantify capillary transport and use the data as basis for modeling of capillary permeability. He also performs quantitative measurements of intracellular calcium using fluorescence microscopy.