Erythrocytes : Oxygen Sensors and Modulators of Vascular Tone

in metabolically active tissue is a fundamental physiological process. Although a number of theories to explain this critical function have been proposed, none have been either universally accepted or fully tested in the intact microcirculation. Any attempt to comprehend the mechanism(s) by which oxygen delivery and metabolic need are matched must, by necessity, be based on the combination of experimental observations and theoretical models. In 1919, August Krogh, in conjunction with a mathematician colleague, K. Erlang, proposed the first oxygen transport model based on the assumption that each capillary is the sole supplier to a cylindrical region of tissue surrounding it (the Krogh cylinder) (55). Under this simple model, oxygen is assumed to diffuse in the radial direction with a uniform diffusivity and to be consumed in the tissue at a uniform constant rate (FIGURE 1A). This model permitted Krogh to propose that capillary density must be actively regulated in response to changing metabolic activity to ensure adequate tissue oxygenation. Specifically, this model predicts that, in response to a fall in oxygen delivery, capillary density would increase to maintain tissue oxygenation. However, no mechanism for this alteration was proposed. Krogh’s model and the interpretations derived from it have continued to influence the way most researchers and clinicians view tissue oxygenation. However, recent studies of microvascular oxygen transport have demonstrated the inadequacies of Krogh’s idealized single capillary model as a comprehensive descriptor of tissue oxygenation. Over 30 years ago, Duling and Berne (19) reported that oxygen levels in the blood diminished along the arteriolar tree with up to two-thirds lost before entering the capillary bed. Numerous researchers, using a variety of techniques in different organs and species, have confirmed this finding (23, 90, 92). Thus it is clear that there is exchange of O2 that occurs among microvessels that is not accounted for by the Krogh model. Although it is not fully understood why there is such a large precapillary decrease in O2, Ellsworth and Pittman (26) provided evidence that some of the O2 leaving the arterioles diffuses to erythrocytes flowing through nearby capillaries, resulting in an increase in their O2 saturation. Since O2 is transported by diffusion from arterioles to capillaries, it is also likely that O2 exchange occurs between capillaries with different O2 levels (23), as proposed in theoretical models (27, 37). This exchange would be consistent with quantitative studies of microvascular blood flow, which have demonstrated considerable spatial heterogeneity of capillary perfusion (93) and a corresponding heterogeneity in O2 delivery. Thus groups of capillaries, rather than the single capillary on which Krogh’s model was based, need to be considered in evaluating the mechanisms responsible for maintaining tissue O2 requirements and uniform O2 delivery. As depicted in FIGURE 1B, the current view is that the microcirculation supplies oxygen to tissue using multiple vessel types that are functionally connected through both convective oxygen flow (blood flow) and diffusive oxygen transfer (23, 37). Inherent in this complexity is the need for a mechanism to direct the convective oxygen flow to regions of the tissue where oxygen is required to satisfy metabolic needs. This directed distribution of peripheral blood flow is analogous to the mechanisms inherent in the pulmonary circulation that direct blood flow to those regions of the lung that are well ventilated (96). One might expect that mechanisms associated with blood flow regulation such as wall shear stress and pressure (myogenic tone) would be sufficient to properly distribute blood flow and, consequently, O2 supply within the arteriolar tree. However, at the microvascular level, total blood flow may not accurately reflect local O2 supply. The convective distribution of oxygen within the arteriolar tree is impacted by the diffusional loss of oxygen to nearby erythrocytes in microvessels. Most of the diffusional loss of oxygen in the arteriole is from erythrocytes near the wall of the vessel, that is, at the edge of the cell free plasma layer. Thus these cells have a lower O2 saturation than those nearer the center of the vessel (9, 25). At vessel bifurcations, this uneven distribution affects convective oxygen supply to a greater or lesser extent depending on the relative flow in the downstream branches. For example, if blood flow into a downstream branch is