{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:58:03Z","timestamp":1791593883965,"version":"4.3.4"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"3","license":[{"start":{"date-parts":[[2020,7,2]],"date-time":"2020-07-02T00:00:00Z","timestamp":1593648000000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,1,21]]},"abstract":"<jats:p>\n                    Carbon dioxide (CO\n                    <jats:sub>2<\/jats:sub>\n                    ), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H\n                    <jats:sup>+<\/jats:sup>\n                    receptor, and endothelial G\u03b1\n                    <jats:sub>q\/11<\/jats:sub>\n                    proteins mediate the CO\n                    <jats:sub>2<\/jats:sub>\n                    \/H\n                    <jats:sup>+<\/jats:sup>\n                    effect on cerebrovascular reactivity in mice. CO\n                    <jats:sub>2<\/jats:sub>\n                    \/H\n                    <jats:sup>+<\/jats:sup>\n                    leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO\n                    <jats:sub>2<\/jats:sub>\n                    , if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO\n                    <jats:sub>2<\/jats:sub>\n                    dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO\n                    <jats:sub>2<\/jats:sub>\n                    effect on anxiety. Even at atmospheric CO\n                    <jats:sub>2<\/jats:sub>\n                    concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO\n                    <jats:sub>2<\/jats:sub>\n                    is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1907467117","type":"journal-article","created":{"date-parts":[[2020,1,2]],"date-time":"2020-01-02T20:06:11Z","timestamp":1577995571000},"page":"1753-1761","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":64,"title":["Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice"],"prefix":"10.1073","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-2439","authenticated-orcid":false,"given":"Jan","family":"Wenzel","sequence":"first","affiliation":[{"name":"Institute for Experimental and Clinical Pharmacology and Toxicology, University of L\u00fcbeck, 23562 L\u00fcbeck, Germany;"},{"name":"DZHK (German Research Centre for Cardiovascular Research), partner site 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Germany;"},{"name":"DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg\/L\u00fcbeck\/Kiel, 23562 L\u00fcbeck, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjestine","family":"Schmidt","sequence":"additional","affiliation":[{"name":"DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg\/L\u00fcbeck\/Kiel, 23562 L\u00fcbeck, Germany;"},{"name":"Institute of Physiology, University of L\u00fcbeck, 23562 L\u00fcbeck, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian C.","family":"Assmann","sequence":"additional","affiliation":[{"name":"Institute for Experimental and Clinical Pharmacology and Toxicology, University of L\u00fcbeck, 23562 L\u00fcbeck, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"St\u00f6lting","sequence":"additional","affiliation":[{"name":"Institute for Experimental and Clinical Pharmacology and Toxicology, University 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