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In 9 out of 10 cases, the molecular cause, however, is unknown. One mechanistic hypothesis involves impaired endothelium-dependent vasodilation through reactive oxygen species (ROS) formation. Indeed, ROS forming NADPH oxidase (\n                    <jats:italic>Nox<\/jats:italic>\n                    ) genes associate with hypertension, yet target validation has been negative. We re-investigate this association by molecular network analysis and identify NOX5, not present in rodents, as a sole neighbor to human vasodilatory endothelial nitric oxide (NO) signaling. In hypertensive patients, endothelial microparticles indeed contained higher levels of NOX5\u2014but not NOX1, NOX2, or NOX4\u2014with a bimodal distribution correlating with disease severity. Mechanistically, mice expressing human\n                    <jats:italic>N<\/jats:italic>\n                    ox5 in endothelial cells developed\u2014upon aging\u2014severe systolic hypertension and impaired endothelium-dependent vasodilation due to uncoupled NO synthase (NOS). We conclude that NOX5-induced uncoupling of endothelial NOS is a causal mechanism and theragnostic target of an age-related hypertension endotype.\n                    <jats:italic>N<\/jats:italic>\n                    ox5 knock-in (KI) mice represent the first mechanism-based animal model of hypertension.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3000885","type":"journal-article","created":{"date-parts":[[2020,11,10]],"date-time":"2020-11-10T15:32:04Z","timestamp":1605022324000},"page":"e3000885","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":45,"title":["NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2437-1773","authenticated-orcid":true,"given":"Mahmoud H.","family":"Elbatreek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sepideh","family":"Sadegh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8701-2295","authenticated-orcid":true,"given":"Elisa","family":"Anastasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3466-6535","authenticated-orcid":true,"given":"Emre","family":"Guney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7535-0417","authenticated-orcid":true,"given":"Cristian","family":"Nogales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5393-2413","authenticated-orcid":true,"given":"Tim","family":"Kacprowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9725-2794","authenticated-orcid":true,"given":"Ahmed A.","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Teubner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Hsun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Yi","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4963-7219","authenticated-orcid":true,"given":"Paul M. 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