The oxygen paradox of neurovascular coupling

Abstract

The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO2). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO2. This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply.

Figure 1

Calculation of pO₂ gradients according to the Krogh model. Under the simplifying assumption of the Krogh–Erlang equation, the pO₂ gradients from the capillary surface to the border of the tissue cylinder are calculated, which would accompany a tissue oxygen consumption of 30 nmoL/(mL/second) at different intercapillary distances. Note that these gradients scale linearly with CMRO₂. The cylindrical shape does not allow for perfect tissue coverage; therefore, the pO₂ gradients into the ‘lethal corners' of the tissue will be a little larger. Diffusion of oxygen in and out of the tissue slice or across the border of the cylinder is not taken into account.