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Explanations for the high CBF versus CMRO<jats:sub>2<\/jats:sub> slope, termed neurovascular coupling (NVC) constant, focused on maintenance of tissue oxygenation to support mitochondrial ATP production. However, paradoxically the brain has a 3\u2010fold lower oxygen extraction fraction (OEF) than other organs with high energy requirements, like heart and muscle during exercise. Here, we hypothesize that the NVC constant and the capillary oxygen mass transfer coefficient (which in combination determine OEF) are co\u2010regulated during activation to maintain simultaneous homeostasis of pH and partial pressure of CO<jats:sub>2<\/jats:sub> and O<jats:sub>2<\/jats:sub> (<jats:italic>p<\/jats:italic>CO<jats:sub>2<\/jats:sub> and <jats:italic>p<\/jats:italic>O<jats:sub>2<\/jats:sub>). To test our hypothesis, we developed an arteriovenous flux balance model for calculating blood and brain pH, <jats:italic>p<\/jats:italic>CO<jats:sub>2<\/jats:sub>, and <jats:italic>p<\/jats:italic>O<jats:sub>2<\/jats:sub> as a function of baseline OEF (OEF<jats:sub>0<\/jats:sub>), CBF, CMRO<jats:sub>2<\/jats:sub>, and proton production by nonoxidative metabolism coupled to ATP hydrolysis. Our model was validated against published brain arteriovenous difference studies and then used to calculate pH, <jats:italic>p<\/jats:italic>CO<jats:sub>2<\/jats:sub>, and <jats:italic>p<\/jats:italic>O<jats:sub>2<\/jats:sub> in activated human cortex from published calibrated fMRI and PET measurements. In agreement with our hypothesis, calculated pH, <jats:italic>p<\/jats:italic>CO<jats:sub>2<\/jats:sub>, and <jats:italic>p<\/jats:italic>O<jats:sub>2<\/jats:sub> remained close to constant independently of CMRO<jats:sub>2<\/jats:sub> in correspondence to experimental measurements of NVC and OEF<jats:sub>0<\/jats:sub>. We also found that the optimum values of the NVC constant and OEF<jats:sub>0<\/jats:sub> that ensure simultaneous homeostasis of pH, <jats:italic>p<\/jats:italic>CO<jats:sub>2<\/jats:sub>, and <jats:italic>p<\/jats:italic>O<jats:sub>2<\/jats:sub> were remarkably similar to their experimental values. Thus, the high NVC constant is overall determined by proton removal by CBF due to increases in nonoxidative glycolysis and glycogenolysis. These findings resolve the paradox of the brain's high CBF yet low OEF during activation, and may contribute to explaining the vulnerability of brain function to reductions in blood flow and capillary density with aging and neurovascular disease.<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\/jnc15839-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15839","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T04:54:22Z","timestamp":1683521662000},"page":"632-662","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Neurovascular coupling is optimized to compensate for the increase in proton production from nonoxidative glycolysis and glycogenolysis during brain activation and maintain homeostasis of pH, <i>p<\/i>CO<sub>2<\/sub>, and <i>p<\/i>O<sub>2<\/sub>"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0181-5597","authenticated-orcid":false,"given":"Mauro","family":"DiNuzzo","sequence":"first","affiliation":[{"name":"Centro Ricerche Enrico Fermi  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8887-3057","authenticated-orcid":false,"given":"Gerald A.","family":"Dienel","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Arkansas for Medical Sciences  Little Rock Arkansas USA"},{"name":"Department of Cell Biology and Physiology University of New Mexico School of Medicine  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1467-0446","authenticated-orcid":false,"given":"Kevin 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