This review addresses classical questions concerning microvascular permeabiltiy in the light of recent experimental work on intact microvascular beds, single perfused microvessels, and endothelial cell cultures. Analyses, based on ultrastructural data from serial sections of the clefts between the endothelial cells of microvessels with continuous walls, conform to the hypothesis that different permeabilities to water and small hydrophilic solutes in microvessels of different tissues can be accounted for by tortuous three-dimensional pathways that pass through breaks in the junctional strands. A fiber matrix ultrafilter at the luminal entrance to the clefts is essential if microvascular walls are to retain their low permeability to macromolecules. Quantitative estimates of exchange through the channels in the endothelial cell membranes suggest that these contribute little to the permeability of most but not all microvessels. The arguments against the convective transport of macromolecules through porous pathways and for the passage of macromolecules by transcytosis via mechanisms linked to the integrity of endothelial vesicles are evaluated. Finally, intracellular signaling mechanisms implicated in transient increases in venular microvessel permeability such as occur in acute inflammation are reviewed in relation to studies of the molecular mechanisms involved in signal transduction in cultured endothelial cells.

Microvascular fluid exchange (flow J(v)) underlies plasma/interstitial fluid (ISF) balance and oedematous swelling. The traditional form of Starling's principle has to be modified in light of insights into the role of ISF pressures and the recognition of the glycocalyx as the semipermeable layer of endothelium. Sum-of-forces evidence and direct observations show that microvascular absorption is transient in most tissues; slight filtration prevails in the steady state, even in venules. This is due in part to the inverse relation between filtration rate and ISF plasma protein concentration; ISF colloid osmotic pressure (COP) rises as J(v) falls. In some specialized regions (e.g. kidney, intestinal mucosa), fluid absorption is sustained by local epithelial secretions, which flush interstitial plasma proteins into the lymphatic system. The low rate of filtration and lymph formation in most tissues can be explained by standing plasma protein gradients within the intercellular cleft of continuous capillaries (glycocalyx model) and around fenestrations. Narrow breaks in the junctional strands of the cleft create high local outward fluid velocities, which cause a disequilibrium between the subglycocalyx space COP and ISF COP. Recent experiments confirm that the effect of ISF COP on J(v) is much less than predicted by the conventional Starling principle, in agreement with modern models. Using a two-pore system model, we also explore how relatively small increases in large pore numbers dramatically increase J(v) during acute inflammation.

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