The microcirculation: physiology at the mesoscale

Abstract

The microcirculation exemplifies the mesoscale in physiological systems, bridging larger and smaller scale phenomena. Microcirculatory research represents an example of a 'middle-out,' rather than 'top-down' or 'bottom-up,' approach to the study of biological function. Computational and mathematical approaches can be used to analyse the functioning of the microcirculation and to establish quantitative relationships between microvascular processes and phenomena occurring on larger and smaller scales, leading to insights which could not be obtained solely by reductionist biological experiments. Given its integrative approach to processes occurring on disparate scales and its emphasis on theoretical as well as experimental approaches, microcirculatory research belongs within current definitions of systems biology.

Figure 1. Schematic illustration of the relationship between the biological phenomena occurring at multiple scales

In some cases, a direct one-to-one link can be established between molecular information and functions or diseases (‘Ideal’). In general, however, interactions between biological processes and mechanisms at a given level of scale or organization influence events occurring on smaller and larger scales (‘Reality’). Theoretical models provide a framework for integrating information within and across biological scales (‘Models’). For example, classical cardiovascular system models can be used to relate the behaviour of the heart and blood vessels to systemic parameters such as blood pressure (A). In neurobiology, theoretical models to predict behaviour of populations of neurons based on the properties of individual neurons are well advanced (B). The development of models for genetic regulatory networks is currently an active field (C). From Secomb et al. (2008), reproduced by permission of John Wiley and Sons.

Figure 2. Computer-generated image of a microvascular network in rat mesentery, illustrating the characteristic structural heterogeneity of the microcirculation

The diverging arteriolar and capillary network fed by the main feeding arteriole (A) is colour-coded according to the generation number, defined as the number of branch points between the main feeding arteriole and a particular vessel. All other vessels are assigned a dark blue colour. The main draining venule is labelled V. The network contains 546 distinct segments (between branch points). Generation numbers of terminal branches (capillaries) range from 3 to 21 in this network. Vessel diameters are doubled in the image, for clarity. The experimental methods used to obtain the structure were described previously (Pries et al. 1995).

Figure 3. Schematic diagram illustrating interactions between factors involved in blood flow regulation

Lines with arrowheads show positive effects and blunt-ended lines show negative effects. Heavy lines show the primary mechanism of metabolic regulation. Pathway a indicates vasodilatation invoked by increased metabolic demand. Pathways b and c indicate secondary effects resulting from increased diameter, causing decreased wall shear stress and increased wall tension. Both of these effects tend to increase arteriolar smooth muscle tone, counteracting the metabolic vasodilatation. Vertical arrows show effects of increasing metabolic demand in the presence of metabolic, shear-dependent and myogenic responses. (+) and (−) indicate the increase or decrease in tone, respectively, generated by each mechanism as a result of increased metabolic demand. A theoretical model based on this scheme was used to obtain quantitative estimates of the effects of these mechanisms on flow regulation. From Arciero et al. (2008), reproduced by permission of the American Physiological Society.

Figure 4. Schematic diagram illustrating interactions between factors involved in structural adaptation of blood vessel diameter and wall thickness

Structural adaptation occurs in response to the haemodynamic forces of wall shear stress (τ) and circumferential wall stress (σ), and a metabolic stimulus, dependent on local oxygen level. Dashed lines indicate relationships dictated by physical laws. Continuous lines indicate biological reactions and associated coefficients show the strengths of these reactions. For example, k_τd and k_md quantify the effects of wall shear stress and the metabolic stimulus on diameter increase. The coefficient k_wτ represents a reduction in sensitivity of vessel diameter change to wall shear stress, with increasing wall thickness. Lines with arrowheads show positive effects and blunt-ended lines show negative effects. A theoretical model based on this scheme predicts distributions of vessel diameters and ratios of vessel diameter to wall thickness consistent with experimental observations and allows estimation of the various coefficients. This model was found to be minimal in the sense that satisfactory agreement with experimental observations could not be obtained if any of the indicated effects were omitted. From Pries et al. (2005), reproduced by permission of Wolters Kluwer Health.