{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:13:51Z","timestamp":1787030031158,"version":"build-2736575974"},"reference-count":71,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:00Z","timestamp":1748476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association Career Development Award","doi-asserted-by":"publisher","award":["24CDA1262486"],"award-info":[{"award-number":["24CDA1262486"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>SARS-CoV-2 can cause neurological issues, including cognitive dysfunction in COVID-19 survivors. Endothelial dysfunction, a key mechanism in COVID-19, is also a risk factor for vascular dementia (VaD). Reduced nitric oxide (NO) bioavailability is a pathogenic factor of endothelial dysfunction and platelet aggregation in COVID-19 patients, and endothelial NO synthase (eNOS) levels decline with advancing age, a risk factor for both COVID-19 morbidity and VaD. SARS-CoV-2 also induces cellular senescence and senescence-associated secretory phenotype (SASP). We hypothesized that eNOS deficiency would worsen neuroinflammation, senescence, blood\u2013brain barrier (BBB) permeability, and hypercoagulability in eNOS-deficient mice. Six-month-old eNOS+\/\u2212 (pre-cognitively impaired experimental VaD) and wild-type (WT) male mice were infected with mouse-adapted (MA10) SARS-CoV-2. Mice were evaluated for weight loss, viral load, and markers of inflammation and senescence 3 days post-infection. eNOS+\/\u2212 mice showed more weight loss (~15%) compared to WT mice (~5%) and increased inflammatory markers (Ccl2, Cxcl9, Cxcl10, IL-1\u03b2, and IL-6) and senescence markers (p53 and p21). They also exhibited higher microglial activation (Iba1) and increased plasma coagulation and BBB permeability, despite comparable lung viral loads and absence of virus in the brain. This is the first experimental evidence demonstrating that eNOS deficiency exacerbates SARS-CoV-2-induced morbidity, neuroinflammation, and brain senescence, linking eNOS to COVID-19-related neuropathology.<\/jats:p>","DOI":"10.3390\/v17060784","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T08:07:58Z","timestamp":1748592478000},"page":"784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["SARS-CoV-2 (MA10) Infection Aggravates Cerebrovascular Pathology in Endothelial Nitric Oxide Synthase-Deficient Mice"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9976-0939","authenticated-orcid":false,"given":"Saifudeen","family":"Ismael","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Research Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshi","family":"Umar","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Research Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake","family":"Ouvrier","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Research Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA"},{"name":"Tulane Brain Institute, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Research Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8852-9675","authenticated-orcid":false,"given":"McKenzie","family":"Cummins","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Tulane University, New Orleans, LA 70118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun","family":"Sapkota","sequence":"additional","affiliation":[{"name":"San Diego Biomedical Research Institute, San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Talkington","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Research Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA"},{"name":"Tulane Brain Institute, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4858-0860","authenticated-orcid":false,"given":"Amanda Louise","family":"White","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Research Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA"},{"name":"Tulane Brain Institute, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Milner","sequence":"additional","affiliation":[{"name":"San Diego Biomedical Research Institute, San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7533-8132","authenticated-orcid":false,"given":"Damir B.","family":"Khismatullin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Tulane University, New Orleans, LA 70118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8969-9553","authenticated-orcid":false,"given":"Gregory","family":"Bix","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Clinical Neuroscience Research Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA"},{"name":"Tulane Brain Institute, Tulane University, New Orleans, LA 70112, USA"},{"name":"Department of Neurology, School of Medicine, Tulane University, New Orleans, LA 70112, USA"},{"name":"Department of Microbiology and Immunology, School of Medicine, Tulane University, New Orleans, LA 70112, USA"},{"name":"School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lopez-Leon, S., Wegman-Ostrosky, T., Perelman, C., Sepulveda, R., Rebolledo, P.A., Cuapio, A., and Villapol, S. 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