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

Abstract

Respiratory-induced changes in the partial pressures of arterial carbon dioxide (P aCO 2 ) and oxygen (P aO 2 ) play a major role in cerebral blood flow (CBF) regulation. Elevations in P aCO 2 (hypercapnia) lead to vasodilatation and increases in CBF, whereas reductions in P aCO 2 (hypocapnia) lead to vasoconstriction and decreases in CBF. A fall in P aO 2 (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 aO 2 and reduces P aCO 2 , 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. The partial pressures of arterial carbon dioxide (P aCO 2 ) and oxygen (P aO 2 ) play a major role in cerebral blood flow (CBF) regulation. Whilst the role of P aCO 2 in the regulation of CBF has been well described (Ainslie & Duffin, 2009), the influence of hypoxia in the regulation of the cerebral circulation has received little focus, especially in humans. This is somewhat surprising given the development of arterial hypoxaemia in both 'normal' physiological endeavours, such as exercise and ascent to high altitude (HA), and during pathology (e.g. chronic lung disease and heart failure). It has been well reported that hypoxia, reflected in a fall in P aO 2 below a certain threshold (<40-45 mmHg), produces cerebral vasodilatation. The mechanisms underling these responses of hypoxia upon CBF, appearing simple at first, are highly complex and involve interactions of many physiological, metabolic and biochemical processes. The major factors underlying the extent of change in CBF during exposure to reductions in P aO 2 are depicted in Fig. 1. These factors, with particular focus on the integrative mechanisms linking reducti...

Cerebral perturbations during exercise in hypoxia

“…An important consideration is that, in addition to blood velocity, changes in diameter of insonated blood vessels could modulate CBF. The middle cerebral artery diameter (the most frequently measured) is nevertheless assumed to remain relatively constant with changes in blood gases and during exercise (4,96), although recent data challenge this assumption in severe hypoxia (118).…”

“…Hypoxia per se is a cerebral vasodilator that increases CBF (24), at least beyond a certain threshold, i.e., arterial oxygen saturation (Sp O 2 )Ͻ 90% or Pa O 2 Ͻ 40 -45 mmHg (4). Hypoxic exposure at rest is associated with some degree of hyperventilation that results in hypocapnia.…”

Cardiovascular Adaptation to High-Altitude Hypoxia

“…In response to acute exposure to high altitude, cerebral blood flow (CBF) rises significantly to ensure an adequate supply of O 2 to meet the brain tissues' large and consistent demand [26][27][28]. The mechanisms underlying the regulation of CBF during short-term HAH are complex and depend partly on the degree of hypoxia per se and on the partial pressures of arterial oxygen (PaO 2 ) and arterial carbon dioxide (PaCO 2 ) [29]. Upon ascent to high altitude, a severe drop in PaO 2 (to <40-45 mmHg) induces a cerebral vasodilation, which suggests that altitude-mediated reduced PaO 2 may act as a cerebral vasodilator.…”

“…In addition to these reflex responses, CBF is also regulated by some other hypoxia-induced changes. For example, high-altitude hypoxia-induced changes of cerebral capillary density, hypoxiainduced factor (HIF), nitric oxide, endothelin-1, reactive oxygen species (ROS), and neurotransmitters may be responsible for the falling CBF during long-term HAH [29].…”

Circulating miRNAs from Dried Blood Spots are Associated with High Altitude Sickness

“…The precise pathogenesis of AMS is not well understood, but hypoxia which affects the regulation of angiogenesis [12] and erythropoietin [13] is likely to be a major factor [14][15][16].…”