{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T13:53:46Z","timestamp":1788357226471,"version":"build-2803163510"},"reference-count":55,"publisher":"Portland Press Ltd.","issue":"7","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,4,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Poor disease outcomes and lethality are directly related to endothelial dysfunction in betacoronavirus infections. Here, we investigated the mechanisms underlying the vascular dysfunction caused by the betacoronaviruses MHV-3 and SARS-CoV-2. Wild-type C57BL\/6 (WT) and knockout mice for inducible nitric oxide synthase (iNOS\u2212\/\u2212) or TNF receptor 1 (TNFR1\u2212\/\u2212) were infected with MHV-3, and K18-hACE2 transgenic mice expressing human ACE2 were infected with SARS-CoV-2. Isometric tension was used to evaluate vascular function. Protein expression was determined by immunofluorescence. Tail-cuff plethysmography and Doppler were used to assess blood pressure and flow, respectively. Nitric oxide (NO) was quantified with the DAF probe. ELISA was used to assess cytokine production. Survival curves were estimated using Kaplan\u2013Meier. MHV-3 infection reduced aortic and vena cava contractility, arterial blood pressure, and blood flow, resulting in death. Resistance mesenteric arteries showed increased contractility. The contractility of the aorta was normalized by removing the endothelium, inhibiting iNOS, genetically deleting iNOS, or scavenging NO. In the aorta, iNOS and phospho-NF-kB p65 subunit expression was enhanced, along with basal NO production. TNF production was increased in plasma and vascular tissue. Genetic deletion of TNFR1 prevented vascular changes triggered by MHV-3, and death. Basal NO production and iNOS expression were also increased by SARS-CoV-2. In conclusion, betacoronavirus induces an endothelium-dependent decrease in contractility in macro-arteries and veins, leading to circulatory failure and death via TNF\/iNOS\/NO. These data highlight the key role of the vascular endothelium and TNF in the pathogenesis and lethality of coronaviruses.<\/jats:p>","DOI":"10.1042\/cs20220663","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T16:27:50Z","timestamp":1679934470000},"page":"543-559","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["TNF\/iNOS\/NO pathway mediates host susceptibility to endothelial-dependent circulatory failure and death induced by betacoronavirus infection"],"prefix":"10.1042","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8635-1642","authenticated-orcid":false,"given":"Ildernandes","family":"Vieira-Alves","sequence":"first","affiliation":[{"name":"1Department of Physiology and Biophysics, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais. Av. Ant\u00f4nio Carlos, 6627, Pampulha. 31270-901, Belo Horizonte - MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonielle\u00a0Rodrigues\u00a0Pereira","family":"Alves","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Biophysics, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais. Av. Ant\u00f4nio Carlos, 6627, Pampulha. 31270-901, Belo Horizonte - MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nat\u00e1lia\u00a0Muradas\u00a0Val\u00e9rio","family":"Souza","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Biophysics, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais. Av. Ant\u00f4nio Carlos, 6627, Pampulha. 31270-901, Belo Horizonte - MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tales\u00a0Leonardo\u00a0de","family":"Melo","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Biophysics, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais. Av. Ant\u00f4nio Carlos, 6627, Pampulha. 31270-901, Belo Horizonte - MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6352-2362","authenticated-orcid":false,"given":"Leda\u00a0Maria\u00a0de\u00a0Castro","family":"Coimbra Campos","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Biophysics, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais. Av. Ant\u00f4nio Carlos, 6627, Pampulha. 31270-901, Belo Horizonte - MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisse\u00a0de\u00a0Souza\u00a0Barbosa","family":"Lacerda","sequence":"additional","affiliation":[{"name":"2Department of Morphology, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais. Av. Ant\u00f4nio Carlos, 6627, Pampulha. 31270-901, Belo Horizonte - MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celso\u00a0Martins","family":"Queiroz-Junior","sequence":"additional","affiliation":[{"name":"2Department of Morphology, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais. Av. 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