Hypoxemia, oxygen content, and the regulation of cerebral blood flow

<jats:p>This review highlights the influence of oxygen (O<jats:sub>2</jats:sub>) availability on cerebral blood flow (CBF). Evidence for reductions in O<jats:sub>2</jats:sub>content (Ca<jats:sub>O<jats:sub>2</jats:sub></jats:sub>) rather than arterial O<jats:sub>2</jats:sub>tension (Pa<jats:sub>O<jats:sub>2</jats:sub></jats:sub>) as the chief regulator of cerebral vasodilation, with deoxyhemoglobin as the primary O<jats:sub>2</jats:sub>sensor and upstream response effector, is discussed. We review in vitro and in vivo data to summarize the molecular mechanisms underpinning CBF responses during changes in Ca<jats:sub>O<jats:sub>2</jats:sub></jats:sub>. We surmise that 1) during hypoxemic hypoxia in healthy humans (e.g., conditions of acute and chronic exposure to normobaric and hypobaric hypoxia), elevations in CBF compensate for reductions in Ca<jats:sub>O<jats:sub>2</jats:sub></jats:sub>and thus maintain cerebral O<jats:sub>2</jats:sub>delivery; 2) evidence from studies implementing iso- and hypervolumic hemodilution, anemia, and polycythemia indicate that Ca<jats:sub>O<jats:sub>2</jats:sub></jats:sub>has an independent influence on CBF; however, the increase in CBF does not fully compensate for the lower Ca<jats:sub>O<jats:sub>2</jats:sub></jats:sub>during hemodilution, and delivery is reduced; and 3) the mechanisms underpinning CBF regulation during changes in O<jats:sub>2</jats:sub>content are multifactorial, involving deoxyhemoglobin-mediated release of nitric oxide metabolites and ATP, deoxyhemoglobin nitrite reductase activity, and the downstream interplay of several vasoactive factors including adenosine and epoxyeicosatrienoic acids. The emerging picture supports the role of deoxyhemoglobin (associated with changes in Ca<jats:sub>O<jats:sub>2</jats:sub></jats:sub>) as the primary biological regulator of CBF. The mechanisms for vasodilation therefore appear more robust during hypoxemic hypoxia than during changes in Ca<jats:sub>O<jats:sub>2</jats:sub></jats:sub>via hemodilution. Clinical implications (e.g., disorders associated with anemia and polycythemia) and future study directions are considered.</jats:p>