The endothelial lining of blood vessels presents a large surface area for exchange of materials between blood and tissues, and is critically involved in many other processes such as regulation of blood flow, inflammatory responses and blood coagulation. It has long been known that the luminal surface of the endothelium is lined with a glycocalyx, a layer of membrane-bound macromolecules which has been determined by electron microscopy to be several tens of nanometers thick. However, investigations in vivo have indicated the presence of a much thicker endothelial surface layer (ESL), with an estimated thickness ranging from 0.5 microm to over 1 microm, that restricts the flow of plasma and can exclude red blood cells and some macromolecular solutes. The evidence for the existence of the ESL, hypotheses about its composition and biophysical properties, its relevance to physiological processes, and its possible clinical implications are considered in this review.

A theoretical model has been developed to simulate blood flow through large microcirculatory networks. The model takes into account the dependence of apparent viscosity of blood on vessel diameter and hematocrit (the Fahraeus-Lindqvist effect), the reduction of intravascular hematocrit relative to the inflow hematocrit of a vessel (the Fahraeus effect), and the disproportionate distribution of red blood cells and plasma at arteriolar bifurcations (phase separation). The model was used to simulate flow in three microvascular networks in the rat mesentery with 436,583, and 913 vessel segments, respectively, using experimental data (length, diameter, and topological organization) obtained from the same networks. Measurements of hematocrit and flow direction in all vessel segments of these networks tested the validity of model results. These tests demonstrate that the prediction of parameters for individual vessel segments in large networks exhibits a high degree of uncertainty; for example, the squared coefficient of correlation between predicted and measured hematocrit of single vessel segments ranges only between 0.15 and 0.33. In contrast, the simulation of integrated characteristics of the network hemodynamics, such as the mean segment hematocrit or the distribution of blood flow velocities, is very precise. In addition, the following conclusions were derived from the comparison of predicted and measured values: 1) The low capillary hematocrits found in mesenteric microcirculatory networks as well as their heterogeneity can be explained on the basis of the Fahraeus effect and phase-separation phenomena. 2) The apparent viscosity of blood in vessels of the investigated tissue with diameters less than 15 microns is substantially higher than expected compared with measurements in glass tubes with the same diameter.

Resistance to blood flow through peripheral vascular beds strongly influences cardiovascular function and transport to tissue. For a given vascular architecture, flow resistance is determined by the rheological behavior of blood flowing through microvessels. A new approach for calculating the contribution of blood rheology to microvascular flow resistance is presented. Morphology (diameter and length), flow velocity, hematocrit, and topological position were determined for all vessel segments (up to 913) of terminal microcirculatory networks in the rat mesentery by intravital microscopy. Flow velocity and hematocrit were also predicted from mathematical flow simulations, in which the assumed dependence of flow resistance on diameter, hematocrit, and shear rate was optimized to minimize the deviation between measured and predicted values. For microvessels with diameters below %z40 ,um, the resulting flow resistances are markedly higher and show a stronger dependence on hematocrit than previously estimated from measurements of blood flow in narrow glass tubes. For example, flow resistance in 10-am microvessels at normal hematocrit is found to exceed that of a corresponding glass tube by a factor of =4. In separate experiments, flow resistance of microvascular networks was estimated from direct measurements of total pressure drop and volume flow, at systemic hematocrits intentionally varied from 0.08 to 0.68. The results agree closely with predictions based on the above-optimized resistance but not with predictions based on glass-tube data. The unexpectedly high flow resistance in small microvessels may be related to interactions between blood components and the inner vessel surface that do not occur in smooth-walled tubes. (Circ Res. 1994;75: 904-915.) Key Words * blood viscosity * peripheral resistancemicrovascular networks * pressure drop * hematocrit E arly in the 19th century direct measurements of arterial and venous blood pressure by Jean Leonard Marie Poiseuille12 revealed that the pressure drop in the circulation occurs mainly in the peripheral vascular bed (the microcirculation), which consists of large numbers of tiny vessels. The microcirculation is therefore the site of most of the resistance to flow, which depends on the architecture of the microvascular network and on the rheological behavior of blood flowing through it. Information about bulk rheological properties of blood has been obtained using rotational viscometers. The findings of such studies, including the nonlinear increase of viscosity with increasing hematocrit and with decreasing shear rate,3-5 have strongly influenced the interpretation of physiological and pathophysiological behavior of the peripheral circulation.However, knowledge of the bulk material properties of blood does not provide a sufficient basis for understanding blood flow through narrow cylindrical tubes. In tubes with diameters >1 mm, the measured apparent viscosities correspond to bulk values from rotational viscometry, but a marked reduction of viscosity is...

We have compared the capillary density and muscle fiber type of musculus vastus lateralis with in vivo insulin action determined by the euglycemic clamp (M value) in 23 Caucasians and 41 Pima Indian nondiabetic men. M value was significantly correlated with capillary density (r = 0.63; P < 0.0001), percent type I fibers (r = 0.29; P < 0.02), and percent type 2B fibers (r = -0.38; P < 0.003). Fasting plasma glucose and insulin concentrations were significantly negatively correlated with capillary density (r = -0.46, P . 0.0001; r = -0.47, P . 0.0001, respectively). Waist circumference/thigh circumference ratio was correlated with percent type 1 fibers (r = -039; P < 0.002). These results suggest that diffusion distance from capillary to muscle cells or some associated biochemical change, and fiber type, could play a role in determining in vivo insulin action. The association of muscle fiber type with body fat distribution may indicate that central obesity is only one aspect of a more generalized metabolic syndrome. The data may provide at least a partial explanation for the insulin resistance associated with obesity and for the altered kinetics of insulin action in the obese.

The effectiveness of anticancer drugs in treating a solid tumour is dependent on delivery of the drug to virtually all cancer cells in the tumour. The distribution of drug in tumour tissue depends on the plasma pharmacokinetics, the structure and function of the tumour vasculature and the transport properties of the drug as it moves through microvessel walls and in the extravascular tissue. The aim of this Review is to provide a broad, balanced perspective on the current understanding of drug transport to tumour cells and on the progress in developing methods to enhance drug delivery. First, the fundamental processes of solute transport in blood and tissue by convection and diffusion are reviewed, including the dependence of penetration distance from vessels into tissue on solute binding or uptake in tissue. The effects of the abnormal characteristics of tumour vasculature and extravascular tissue on these transport properties are then discussed. Finally, methods for overcoming limitations in drug transport and thereby achieving improved therapeutic results are surveyed.

The apparent viscosity of blood in glass tubes declines with decreasing diameter (Fåhraeus-Lindqvist effect) and exhibits a distinctive minimum at 6-7 microm. However, flow resistance in vivo in small vessels is substantially higher than predicted by in vitro viscosity data. The presence of a thick endothelial surface layer (ESL) has been proposed as the primary cause for this discrepancy. Here, a physical model is proposed for microvascular flow resistance as a function of vessel diameter and hematocrit in vivo; it combines in vitro blood viscosity with effects of a diameter-dependent ESL. The model was developed on the basis of flow distributions observed in three microvascular networks in the rat mesentery with 392, 546, and 383 vessel segments, for which vessel diameters, network architecture, flow velocity, and hematocrit were determined by intravital microscopy. A previously described hemodynamic simulation was used to predict the distributions of flow and hematocrit from the assumed model for effective blood viscosity. The dependence of ESL thickness on vessel diameter was estimated by minimizing deviations of predicted values for velocities, flow directions, and hematocrits from measured data. Optimal results were obtained with a layer thickness of approximately 0.8-1 microm for 10- to 40-microm-diameter vessels and declined strongly for smaller diameters, with an additional hematocrit-dependent impact on flow resistance exhibiting a maximum for approximately 10-microm-diameter vessels. These results show that flow resistance in vivo can be explained by in vitro blood viscosity and the presence of an ESL and indicate the rheologically effective thickness of the ESL in microvessels.

We consider the motion of red blood cells and other non-spherical microcapsules dilutely suspended in a simple shear flow. Our analysis indicates that depending on the viscosity, membrane elasticity, geometry and shear rate, the particle exhibits either tumbling, tank-treading of the membrane about the viscous interior with periodic oscillations of the orientation angle, or intermittent behavior in which the two modes occur alternately. For red blood cells, we compute the complete phase diagram and identify a novel tank-treading-to-tumbling transition at low shear rates. Observations of such motions coupled with our theoretical framework may provide a sensitive means of assessing capsule properties. 1Human red blood cells suspended at low concentrations in steady simple shear flow have been observed to exhibit two types of motion. While cells suspended in a low viscosity media tumble continuously, cells suspended in a fluid with sufficiently high viscosity exhibit 'tank-treading' motion [1]. Here, we use the term tank-treading to describe a cell that maintains almost constant shape and orientation in the laboratory frame, but whose membrane circulates around the interior much like the motion of a tank tread. Keller and Skalak [2] analyzed the motion of a tank-treading viscous ellipsoid and concluded that the behavior depends on the ratio of the viscosities of the inner and outer fluids and was independent of the shear rate. However, it has recently been observed that red blood cells oscillate about a fixed angle while tank-treading and that tumbling can be induced by lowering the shear rate [3]. Furthermore, the dynamics of synthetic microcapsules in simple shear flow have been shown to depend not only on the viscosity ratio, but also on the shear rate: at high shear rates, the capsule surface tank-treads about the interior while the orientation oscillates; at low shear rates, the capsule tumbles [4, 5]. These observations are unaccounted for by current theory and motivate the present work. In this letter, we provide a unified theoretical framework for analyzing the motion of both non-spherical capsules and red blood cells in simple shear flow and attribute the observed shear rate dependent behavior to a periodic variation in the elastic energy during tank-treading.Here, we model the cell or capsule as an ellipsoid of viscosity µ ′ contained in an elastic membrane and immersed in a fluid of viscosity µ. In the frame of the ellipsoid having axes of length a i , the surface is at the position x 2 i a 2 i = 1. The external flow unperturbed by the ellipsoid is a simple shear flow of rateγ in the laboratory reference frame (see figure 1a).We assume that material elements in the membrane move along elliptical paths in planes parallel to the x 1 -x 2 plane, with velocity field as in [2]. Then, the position of each membrane element is defined by a phase angle φ(t) and the tank-treading frequency is ∂ t φ(t). When φ = 2π a point on the surface has returned to its starting point. Our formulation extends the ana...

Hemodynamic parameters were determined in each vessel segment of six complete microvascular networks in the rat mesentery by using a combination of experimental measurements and theoretical stimulations. For a total number of 2592 segments, a strong unified dependence of wall shear stress on intravascular pressure for arterioles, capillaries, and venules was obtained. All three types of segments exhibit an essentially identical variation of shear stress from high to low values (from approximately 100 to 10 dyne/cm2) as intravascular pressure falls from 70 to 15 mm Hg. On the basis of these observations, it is proposed that vascular beds grow and adapt so as to maintain the shear stress in each vessel at a level that depends on local transmural pressure. In contrast to Murray's classic 'minimum-cost' hypothesis, which implies uniformity of wall shear rate throughout the vasculature, the proposed design principle provides an explanation for the functionally important arteriovenous asymmetry of wall shear rates and flow resistance in the circulation.