Regulation of cerebral blood flow in mammals during chronic hypoxia: a matter of balance

Respiratory-induced changes in the partial pressures of arterial carbon dioxide (P-aCO2) and oxygen (P-aO2) play a major role in cerebral blood flow (CBF) regulation. Elevations in P-aCO2 (hypercapnia) lead to vasodilatation and increases in CBF, whereas reductions in P-acO2 (hypocapnia) lead to vasoconstriction and decreases in CBF. A fall in P-aO2 (hypoxia) below a certain threshold (< 40-45 mmHg) also produces cerebral vasodilatation. Upon initial exposure to hypoxia, CBF is elevated via a greater relative degree of hypoxia compared with hypocapnia. At this point, hypoxia-induced elevations in blood pressure and loss of cerebral autoregulation, stimulation of neuronal pathways, angiogenesis, release of adenosine, endothelium-derived NO and a variety of autocoids and cytokines are additional factors acting to increase CBF. Following 2-3 days, however, the process of ventilatory acclimatization results in a progressive rise in ventilation, which increases P-aO2 and reduces P-aCO2, collectively acting to attenuate the initial rise in CBF. Other factors acting to lower CBF include elevations in haematocrit, sympathetic nerve activity and local and endothelium-derived vasoconstrictors. Hypoxia-induced alterations of cerebrovascular reactivity, autoregulation and pulmonary vascular tone may also affect CBF. Thus, the extent of change in CBF during exposure to hypoxia is dependent on the balance between the myriad of vasodilators and constrictors derived from the endothelium, neuronal innervations and perfusion pressure. This review examines the extent and mechanisms by which hypoxia regulates CBF. Particular focus will be given to the marked influence of hypoxia associated with exposure to high altitude and chronic lung disease. The associated implications of these hypoxia-induced integrative alterations for the regulation of CBF are discussed, and future avenues for research are proposed.