ABSTRACT

The microcirculation is comprised of blood vessels (arterioles, capillaries, and venules) with diameters of less than approximately 150 μm. The importance of the microcirculation is underscored by the fact that most of the hydrodynamic resistance of the circulatory system lies in the microvessels (especially in arterioles) and most of the exchange of nutrients and waste products occurs at the level of the smallest microvessels. The subjects of microcirculatory research are blood flow and molecular transport in microvessels, mechanical interactions and molecular exchange between these vessels and the surrounding tissue, and regulation of blood flow and pressure and molecular transport. Quantitative knowledge of microcirculatory mechanics and mass transport has been accumulated primarily in the past 30 years owing to significant innovations in methods and techniques to measure microcirculatory parameters and methods to analyze microcirculatory data. The development of these methods has required joint efforts of physiologists and biomedical engineers. Key innovations include significant improvements in

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intravital microscopy, the dual-slit method (Wayland-Johnson) for measuring velocity in microvessels, the servo-null method (Wiederhielm-Intaglietta) for measuring pressure in microvessels, the recessed oxygen microelectrode (Whalen) for polarographic measurements of partial pressure of oxygen, and the microspectrophotometric method (Pittman-Duling) for measuring oxyhemoglobin saturation in microvessels. The single-capillary cannulation method (Landis-Michel) has provided a powerful tool for studies of transport of water and solutes through the capillary endothelium. In the last decade, new experimental techniques have appeared, many adapted from cell biology and modified for in vivo studies, that are having a tremendous impact on the field. Examples include confocal and multiphoton microscopy for better three-dimensional resolution of microvascular structures, methods of optical imaging using fluorescent labels (e.g., labeling blood cells for velocity measurements) and fluorescent dyes (e.g., calcium ion and nitric oxide sensitive dyes for measuring their dynamics in vascular smooth muscle, endothelium, and surrounding tissue cells in vivo), development of sensors (glass filaments, optical and magnetic tweezers) for measuring forces in the nanonewton range that are characteristic of cell-cell interactions, phosphorescence decay measurements as an indicator of oxygen tension, and methods of manipulating receptors on the surfaces of blood cells and endothelial cells. In addition to the dramatic developments in experimental techniques, quantitative knowledge and understanding of the microcirculation have been significantly enhanced by theoretical studies, perhaps having a larger impact than in other areas of physiology. Extensive theoretical work has been conducted on the mechanics of the red blood cell (RBC) and leukocyte; mechanics of blood flow in single microvessels and microvascular networks, oxygen (O2), carbon dioxide (CO2), and nitric oxide (NO) exchange between microvessels and surrounding tissue; and water and solute transport through capillary endothelium and the surrounding tissue [1,2]. These theoretical studies not only aid in the interpretation of experimental data, but in many cases also serve as a framework for quantitative testing of working hypotheses and as a guide in designing and conducting further experiments. The accumulated knowledge has led to significant progress in our understanding of mechanisms of regulation of blood flow and molecular exchange in the microcirculation in many organs and tissues under a variety of physiological and pathological conditions (e.g., hypoxia, hypertension, sickle cell anemia, diabetes, inflammation, hemorrhage, ischemia/reperfusion, sepsis, cancer). Discussions are under way to organize the enormous amount of information on the microcirculation in the form of a database or a network of databases encompassing anatomical and functional data, and conceptual (pathway) and computational models. This effort is referred to as the Microcirculation Physiome Project, a subset of the Physiome Project [3].