Behavioral, respiratory and metabolic consequences of impaired cerebrovascular reactivity

Carbon dioxide (CO2) and protons (H+) have a strong influence on cerebral perfusion, but the function of this is not clear yet. Here, we found that GPR4, a receptor for H+ in the vasculature, sensed CO2/H+ and that an endothelial Gαq/11-dependent signaling pathway mediated the CO2/H+ effect on cerebrovascular reactivity. While CO2/H+-induced Gαq/11 signaling constricted vessels in the retrotrapezoid nucleus, it had a dilative effect in other brain areas explaining why loss of cerebrovascular reactivity in mice differentially modulated CO2 effects: it reduced respiration but aggravated behavioral and metabolic responses to CO2. Even with normal CO2 concentrations mice with impaired cerebrovascular reactivity were more anxious and showed metabolic changes indicating that cerebrovascular reactivity is essential for normal physiology.