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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\u2010mediated signaling and inhibition of ATP\u2010sensitive potassium (K<jats:sub>ATP<\/jats:sub>) 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 \u223c50% of the response) involves the actions of adenosine and modulation of vascular K<jats:sub>ATP<\/jats:sub> channels. However, recruitment of other vasodilatory signaling mechanisms is required for the full expression of the cerebrovascular response to hypoxia.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16146-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1113\/jp285060","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T19:51:13Z","timestamp":1717703473000},"page":"2263-2280","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["On the mechanisms of brain blood flow regulation during hypoxia"],"prefix":"10.1113","volume":"603","author":[{"given":"Alexander","family":"Mascarenhas","sequence":"first","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology &amp; Pharmacology University College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Braga","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology &amp; Pharmacology University College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Maria","family":"Majernikova","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology &amp; Pharmacology University College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shereen","family":"Nizari","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology &amp; Pharmacology University College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Marletta","sequence":"additional","affiliation":[{"name":"Main Library University College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5751-8829","authenticated-orcid":false,"given":"Shefeeq M.","family":"Theparambil","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology &amp; Pharmacology University College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7636-6813","authenticated-orcid":false,"given":"Qadeer","family":"Aziz","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology &amp; Pharmacology University College London  London United Kingdom"},{"name":"Translational Medicine and Therapeutics, William Harvey Research Institute Queen Mary University of London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nephtali","family":"Marina","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology &amp; Pharmacology University College London  London United Kingdom"},{"name":"Division of Medicine University College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3068-491X","authenticated-orcid":false,"given":"Alexander V.","family":"Gourine","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology &amp; Pharmacology University College London  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,6]]},"reference":[{"issue":"1","key":"e_1_2_2_2_1","first-page":"H226","article-title":"Opioids and nitric oxide contribute to hypoxia\u2010induced pial arterial vasodilation in newborn pigs","volume":"268","author":"Armstead W. 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