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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Two methods are described for measuring the filtration coefficient of individually perfused frog mesenteric capillaries. Both methods involve the perfusion of capillaries via a micropipette with a solution in which a small number of human red cells are suspended. After a short period of perfusion, the capillary is occluded at a point some 500 ,um or more downstream from the point of cannulation. Movements of the red cells in the isolated capillary micropipette system are interpreted to be the consequence of fluid movements across the capillary wall. The filtration coefficient of the capillary is determined either (method I) from a series of different filtration rates measured at different capillary hydrostatic pressures when intracapillary colloid osmotic pressure is constant, or (method II) from the changes in filtration rate as the fluid within the capillary concentrates at a constant pressure. Values for the filtration coefficient obtained by both methods have a skewed distribution. Determinations made by method I at 14-16°C have a peak value of 2 x 10-3 vm.sec-1 . cm H20-1 and determinations made by method II at 22-26°C have a peak value of 5 x 10-3sjm . sec-. cm H20 -1.The assumptions underlying both methods are discussed and a mathematical model of the change in protein concentration in a closed off capillary at constant pressure is presented in the appendix.In 1927, Landis reported the first quantitative measurements of the rate of filtration and reabsorption of water across the capillary walls. He occluded single capillaries of the frog mesentery with a glass micro rod and observed that on some occasions red cells within the capillary moved towards the point of occlusion and on other occasions they moved away from it. He deduced that a red cell moved towards the point of occlusion when fluid was filtered across the capillary wall out of the column of plasma between that red cell and the point of occlusion. When fluid was reabsorbed from the tissues into the plasma, the column of plasma in an occluded capillary expanded leading the suspended red cells to move away from the site of occlusion. Measuring the capillary pressure by direct micropuncture, Landis was able to obtain a correlation between the rates of filtration and reabsorption of fluid across capillary walls and the capillary pressure. In this way he estimated an average figure for the filtration coefficient or hydraulic conductivity of the capillary wall for a population of capillaries.In

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In the rat trachea, substance P causes rapid but transient plasma leakage. We sought to determine how closely the number, morphology, and size of endothelial gaps correspond to the time course of this leakage. Endothelial gaps were examined by scanning electron microscopy (EM), by transmission EM, or by light microscopy after silver nitrate staining. Substance P-induced leakage of the particulate tracer Monastral blue peaked at 1 min but decreased with a half-life of 0.3 min. The number of silver-stained gaps also peaked at 1 min then decreased significantly more slowly (half-life 1.9 min) than the leakage. Scanning EM revealed two types of endothelial gaps, designated vertical gaps and oblique slits. Vertical gaps predominated at peak leakage, whereas oblique slits became more common as the leakage diminished. Measurements of the mean diameter of vertical gaps made by light microscopy, scanning EM, and transmission EM were all in the range of 0.36-0.47 micron. Fingerlike endothelial cell processes that appeared during gap formation became shorter as the leakage diminished (mean length: 1.44 microns at 1 min compared with 1.06 microns at 3 min after substance P), suggesting a role in gap closure. We conclude that the plasma leakage occurring immediately after an inflammatory stimulus results from the rapid formation of endothelial gaps. Multiple factors, including alterations in gap morphology, gap closure, and changes in driving force, are likely to participate in the rapid decrease in the leakage.

SUMMARY1. Direct measurements of the capillary pressure (Pa) were made in capillaries at the base of the nails of the fingers and toes of two subjects (the authors of this paper).2. With the hand or foot at heart level, Pc varied over the range of 7-70 cm H20 with mean values of 43 cm H20 in both the fingers and the toes. Pc was higher in the arterial limb (mean 49 cm H20) than in the venous limb (mean 34 cm H20) of the capillary loops. The plasma colloid osmotic pressures for the two subjects were 33 and 34 cm H20.3. For capillaries at heart level there was a strong positive correlation between Pc and skin temperature when the latter was varied over the range 23-36 0C.4. When the hand or foot was lowered, P, increased less than the local arterial (Pa) and venous pressures (Pv). Furthermore the variation in P, was reduced. In fourteen measurements of P, made on capillaries in the toes of standing subjects, Pc was no more than 10 cm H20 greater than P, It is argued that the increase in the ratio (Pa -P,)/(P, -Pv) with hydrostatic load represents an increase in the ratio of pre-to post-capillary resistance.5. When Pv was increased by inflating a sphygmomanometer cuff around the upper arm, (Pa-P,)/(P, -Pv) increased in the hand held at heart level. These changes were similar to those seen with changes in position.6. The implications of the results are discussed with respect to fluid balance between the blood and tissues. It is argued that since P, in the warm hand was never less than the plasma colloid osmotic pressure, fluid is not reabsorbed from the tissues into the capillaries of the warm skin of the hand even at heart level. Compensatory changes in the circulation appear to minimise the filtration of fluid into the feet of the standing subject but the mechanism of these changes remains obscure.