Always Enough but Never Too Much: The How and Why of Down Regulating Tissue Oxygenation

Cardiovascular regulation of tissue oxygenation is generally viewed as an anti-drop process that prevents tissue oxygen concentration from falling below some minimum. I propose that cardiovascular regulation is predominately an anti-rise process designed to down-regulate oxygen delivery. This maintains an evolutionarily-conserved, reduced intracellular environment to prevent oxidation of redox-sensitive regulatory protein thiols. A number of points support this hypothesis. 1) Oxygen is the only nutrient with a positive, four-fold diffusion gradient from the environment to systemic tissues, minimizing the likelyhood that oxygen delivery is limited. 2) Hemoglobin (Hb) retains oxygen unless offloading is absolutely necessary. The allosteric properties of (Hb) keep oxygen tightly bound until absolutely needed and the Bohr shift, which favors offloading, is only transient and lost when metabolism is restored. 3) A myoglobin-like Hb (xHb) would offload all of its oxygen and could easily have evolved, but it did not. 4) Oxygen-sensitive vasoconstrictors and hyperoxic-rarefaction prevent acute and chronic over perfusion. 5) Fåhræus and Fåhræus Linqvist effects reduce capillary hematocrit to minimize microcirculatory oxygen content. 6) Venous blood remains 75% saturated, wasting 75% of cardiac output were an oxygen reserve it not needed. 7) xHb-containing red blood cells could be considerably smaller and thereby decrease Fåhræus and Fåhræus Linqvist effects and cardiac load. In summary, the capacity of the cardiovascular system to deliver oxygen to the tissues generally exceeds demand and while maintenance of an oxygen delivery reserve is important, it is more important to prevent excess oxygen delivery.