On the mechanisms of brain blood flow regulation during hypoxia

Mascarenhas, Alexander and Braga, Alice and Majernikova, Sara Maria and Nizari, Shereen and Marletta, Debora and Theparambil, Shefeeq M. and Aziz, Qadeer and Marina, Nephtali and Gourine, Alexander V. (2024) On the mechanisms of brain blood flow regulation during hypoxia. The Journal of Physiology. ISSN 0022-3751

Abstract

The brain requires an uninterrupted supply of oxygen and nutrients to support the high metabolic needs of billions of nerve cells processing information. In low oxygen conditions, increases in cerebral blood flow maintain brain oxygen delivery, but the cellular and molecular mechanisms responsible for dilation of cerebral blood vessels in response to hypoxia are not fully understood. This article presents a systematic review and analysis of data reported in studies of these mechanisms. Our primary outcome measure was the percent reduction of the cerebrovascular response to hypoxia in conditions of pharmacological or genetic blockade of specific signaling mechanisms studied in experimental animals or in humans. Selection criteria were met by 28 articles describing the results of animal studies and six articles describing the results of studies conducted in humans. Selected studies investigated the potential involvement of various neurotransmitters, neuromodulators, vasoactive molecules and ion channels. Of all the experimental conditions, blockade of adenosine-mediated signaling and inhibition of ATP-sensitive potassium (KATP) channels had the most significant effect in reducing the cerebrovascular response to hypoxia (by 49% and 37%, respectively). Various degree reductions of the hypoxic response were also reported in studies which investigated the roles of nitric oxide, arachidonic acid derivates, catecholamines and hydrogen sulphide, amongst others. However, definitive conclusions about the importance of these signaling pathways cannot be drawn from the results of this analysis. In conclusion, there is significant evidence that one of the key mechanisms of hypoxic cerebral vasodilation (accounting for ∼50% of the response) involves the actions of adenosine and modulation of vascular KATP channels. However, recruitment of other vasodilatory signaling mechanisms is required for the full expression of the cerebrovascular response to hypoxia.