{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:04:06Z","timestamp":1770289446113,"version":"3.49.0"},"reference-count":21,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T00:00:00Z","timestamp":1626739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>We report the case of a 77-year-old woman affected by coronavirus disease-19 (COVID-19) who developed an occlusive arterial disease of the lower limb requiring a left leg amputation. We studied the mechanisms of vascular damage by SARS-CoV-2 by means of a comprehensive multi-technique in situ analysis on the diseased popliteal arterial district, including immunohistochemistry (IHC), transmission electron microscopy (TEM) and miRNA analysis. At histological analyses, we observed a lymphocytic inflammatory infiltrate, oedema and endothelialitis of adventitial vasa vasorum while the media was normal and the intima had only minor changes. The vasa vasorum expressed the ACE2 receptor and factor VIII; compared with the controls, VEGFR2 staining was reduced. TEM analyses showed endothelial injury and numerous Weibel\u2013Palade bodies in the cytoplasm. No coronavirus particle was seen. IL-6 protein and mRNA, together with miR-155-5p and miRs-27a-5p, which can target IL-6, were significantly increased compared with that in the controls. Our case report suggests an involvement of adventitial artery microcirculation by inflammation in the course of COVID-19. Without evident signs of current infection by SARS-CoV-2, endothelial cells show a spectrum of structural and functional alterations that can fuel the cardiovascular complications observed in people infected with SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/biom11071063","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T11:26:10Z","timestamp":1626780370000},"page":"1063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Adventitial Microcirculation Is a Major Target of SARS-CoV-2-Mediated Vascular Inflammation"],"prefix":"10.3390","volume":"11","author":[{"given":"Francesco","family":"Vasuri","sequence":"first","affiliation":[{"name":"Pathology Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6465-9945","authenticated-orcid":false,"given":"Carmen","family":"Ciavarella","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6262-8173","authenticated-orcid":false,"given":"Salvatore","family":"Collura","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Mascoli","sequence":"additional","affiliation":[{"name":"Vascular Surgery Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Valente","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessio","family":"Degiovanni","sequence":"additional","affiliation":[{"name":"Pathology Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauro","family":"Gargiulo","sequence":"additional","affiliation":[{"name":"Vascular Surgery Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Capri","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy"},{"name":"Interdepartmental Center \u201cAlma Mater Research Institute on Global Challenges and Climate Change (Alma Climate)\u201d, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1506-1829","authenticated-orcid":false,"given":"Gianandrea","family":"Pasquinelli","sequence":"additional","affiliation":[{"name":"Pathology Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,20]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2020, March 01). Coronavirus Disease (COVID-19) Outbreak. Available online: https:\/\/www.who.int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1016\/j.jacc.2020.03.031","article-title":"Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic","volume":"75","author":"Driggin","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1093\/cvr\/cvaa106","article-title":"COVID-19 and the cardiovascular system: Implications for risk assessment, diagnosis, and treatment options","volume":"116","author":"Guzik","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1111\/jth.14888","article-title":"Incidence of venous thromboembolism in hospitalized patients with COVID-19","volume":"18","author":"Middeldorp","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis","volume":"203","author":"Hamming","year":"2004","journal-title":"J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1093\/cvr\/cvaa006","article-title":"Treatment of coronary microvascular dysfunction","volume":"116","author":"Pepine","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"636843","DOI":"10.3389\/fcvm.2021.636843","article-title":"Microvascular Angiopathic Consequences of COVID-19","volume":"8","author":"Nalugo","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1016\/S0140-6736(98)11415-0","article-title":"Prediction of benefit from carotid endarterectomy in individual patients: A risk-modelling study. European Carotid Surgery Trialists\u2019 Collaborative Group","volume":"353","author":"Rothwell","year":"1999","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0741-5214(97)70045-4","article-title":"Recommended standards for reports dealing with lower extremity ischemia: Revised version","volume":"26","author":"Rutherford","year":"1997","journal-title":"J. Vasc. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"855","DOI":"10.2337\/diacare.21.5.855","article-title":"Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation","volume":"21","author":"Armstrong","year":"1998","journal-title":"Diabetes Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.arr.2013.05.001","article-title":"MicroRNAs Linking Inflamm-Aging, Cellular Senescence and Cancer","volume":"12","author":"Olivieri","year":"2013","journal-title":"Ageing Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110415","DOI":"10.1016\/j.mehy.2020.110415","article-title":"Tackling the COVID-19 \u201ccytokine storm\u201d with microRNA mimics directly targeting the 3\u2032UTR of pro-inflammatory mRNAs","volume":"146","author":"Gasparello","year":"2021","journal-title":"Med. Hypotheses"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1161\/CIRCRESAHA.120.317015","article-title":"Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2","volume":"126","author":"Gheblawi","year":"2020","journal-title":"Circ. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial cell infection and endotheliitis in COVID-19","volume":"395","author":"Varga","year":"2020","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1161\/CIRCRESAHA.120.317447","article-title":"The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications","volume":"127","author":"McFadyen","year":"2020","journal-title":"Circ. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1056\/NEJMoa2015432","article-title":"Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in COVID-19","volume":"383","author":"Ackermann","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1007\/s00134-020-06062-x","article-title":"High risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study","volume":"46","author":"Helms","year":"2020","journal-title":"Intensive Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.1016\/S0140-6736(20)31188-0","article-title":"Electron microscopy of SARS-CoV-2: A challenging task","volume":"395","author":"Goldsmith","year":"2020","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.7150\/ijbs.45498","article-title":"Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19","volume":"16","author":"Yang","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_20","first-page":"S351","article-title":"COVID-19 Pandemic\u2014A Narrative Review of the Potential Roles of Chloroquine and Hydroxychloroquine","volume":"23","author":"Almeida","year":"2020","journal-title":"Pain Physician"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"613422","DOI":"10.3389\/fimmu.2021.613422","article-title":"Interleukin-6 Is a Biomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia","volume":"12","author":"Oliveira","year":"2021","journal-title":"Front. 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