Fig. 1: Summary data illustrating the outcome of systematic review and analysis of data reported in studies that investigated the signaling mechanisms underlying the cerebrovascular response to CO₂.

Individual data points illustrate the percent reduction of the cerebrovascular response to CO₂ in conditions of pharmacological or genetic blockade of hypothesized signaling pathways, reported in published studies involving in vivo animal models and human participants. Color gradient and the size of each symbol denote the statistical power of each individual study (total study n). Black symbols illustrate the mean (with 95% confidence intervals) reduction of CO₂-induced cerebrovascular response observed under experimental conditions (214 in total, reported in 131 primary sources; Supplementary Table 1) grouped into categories of studies targeting specific signaling pathways. The effects of indomethacin are analyzed and shown in a separate category as inhibition of cerebrovascular CO₂ reactivity by this drug is greater compared to that of other non-specific cyclooxygenase inhibitors. Multiple category includes the results of experimental studies that targeted several signaling pathways simultaneously. COX cyclooxygenase, nNOS neuronal nitric oxide synthase, NOS nitric oxide synthase, PG prostaglandin, cGMP cyclic guanosine monophosphate, AA arachidonic acid, ROS reactive oxygen species. Source data are provided as a Source Data file.