Altitude acclimatization, hemoglobin-oxygen affinity, and circulatory oxygen transport in hypoxia

Abstract

In mammals and other air-breathing vertebrates that live at high altitude, adjustments in convective O₂ transport via changes in blood hemoglobin (Hb) content and/or Hb-O₂ affinity can potentially mitigate the effects of arterial hypoxemia. However, there are conflicting views about the optimal values of such traits in hypoxia, partly due to the intriguing observation that hypoxia-induced acclimatization responses in humans and other predominantly lowland mammals are frequently not aligned in the same direction as evolved phenotypic changes in high-altitude natives. Here we review relevant theoretical and empirical results and we highlight experimental studies of rodents and humans that provide insights into the combination of hematological changes that help attenuate the decline in aerobic performance in hypoxia. For a given severity of hypoxia, experimental results suggest that optimal values for hematological traits are conditional on the states of other interrelated phenotypes that govern different steps in the O₂-transport pathway.

Keywords: Aerobic performance; High-altitude adaptation; Hypoxia; Oxygen transport pathway; VO(2max).

Figure 1.

Schematic illustration of blood O₂ transport. (A) O₂-equilibrium curve under the physicochemical conditions prevailing in arterial blood (a, solid curve, open symbol) and venous blood (v, dashed curve, closed symbol). The curve is a plot of blood O₂ content (y-axis) versus PO₂ (x-axis), with paired values for arterial and venous blood connected by a solid line. C_aO₂ - C_vO₂ denotes the arterial–venous difference in blood O₂ content, P_aO₂ - P_vO₂ denotes the corresponding difference in PO₂, βbO₂ denotes the blood O₂ capacitance coefficient (see text for details), Q denotes cardiac output, and VO₂ denotes the rate of O₂ consumption. On the right-hand side of the graph, the area of the rectangle is proportional to total O₂ consumption, which can be enhanced by increasing Q and/or by increasing βbO_2. Increases in βbO₂ produce a corresponding increase in C_aO₂ - C_vO₂ through shifts in the shape or position of the O₂-equilibrium curve.

Figure 2.

O₂-equilibrium curves showing the effect of changes in Hb-O₂ affinity on tissue O₂ delivery under conditions of normoxia (A) and hypoxia (B). In panel B, the PO₂ for venous blood (P_vO₂) is marked by a vertical grey line that extends to the x-axis. P₅₀, the PO₂ at which Hb is 50% saturated. Each change in Hb-O₂ affinity produces a shift in P_vO₂, but the PO₂ of arterial blood (P_aO₂) is assumed to remain constant. Note that in normoxia (A) the right-shifted curve maximizes βbO₂ and preserves a higher P_vO₂ (an overall index of tissue oxygenation). In hypoxia, by contrast, the left-shifted curve maximizes βbO₂ and preserves a higher P_vO₂ relative to the right-shifted curve.

Figure 3.

Johansen plots showing how traits that govern circulatory O₂ delivery and tissue O₂ extraction contribute to VO₂max in Sprague-Dawley rats. Data are shown for rats tested in normoxia (A) and hypoxia (B). Left-hand panels show O₂-equilbrium curves based on data for the control group (solid black line) and the treatment group with pharmacologically increased Hb-O₂ affinity (solid grey line). In both A and B, the area of the box in the right-hand panel denotes VO₂max elicited by aerobic exercise (value inside the box in ml min⁻¹ g⁻¹). Graphs were plotted using data from experimental groups 2 and 3 in Henderson et al. (2000).

Figure 4.

Johansen plot showing how traits that govern circulatory O₂ delivery and tissue O₂ extraction contribute to hypoxic VO₂max in highland deer mice (Permomyscus maniculatus) and lowland white-footed mice (P. leucopus). The left-hand panel shows O₂-equilbrium curves based on data for highland deer mice (grey) and lowland white-footed mice (black). In the right-hand panel, the area of the box denotes thermogenic VO₂max elicited by cold exposure (value inside the box in ml min⁻¹ g⁻¹). Replicated from Wearing and Scott (2021) and based on experimental data from Tate et al. (2020) and Ivy et al. (2020).

Figure 5.

Effects of increasing tissue O₂ diffusing capacity (D_TO₂) on hypoxic VO₂max and blood PO₂’s inferred from mathematical modeling of the O₂-transport pathway in deer mice. (A) Relative changes in hypoxic VO₂max and (B) changes in alveolar (P_AO₂), arterial (P_aO₂), and venous (PvO₂) in response to relative increases in D_TO₂. Effects were modeled using blood P₅₀’s of deer mice with representative high- and low-altitude Hb genotypes (mean values and standard errors of the mean are denoted with bold and fine lines, respectively). Reproduced from Wearing et al. (2021).

Figure 6.

Relationship between the change in VO_2max between exercise trials in normoxia vs. hypoxia and the corresponding change in oxyHb saturation. Data are for human subjects with normal or high-affinity Hbs. Reproduced with permission from Dominelli et al. (2020).