{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:27:12Z","timestamp":1793316432255,"version":"4.5.0"},"reference-count":71,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Esp\u00edrito Santo Research and Innovation Support Foundation (FAPES)","award":["No. 984\/2022"],"award-info":[{"award-number":["No. 984\/2022"]}]},{"name":"Esp\u00edrito Santo Research and Innovation Support Foundation (FAPES)","award":["No. 723\/2024"],"award-info":[{"award-number":["No. 723\/2024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Copper is an essential micronutrient required for physiological functions, but elevated serum levels impair vascular reactivity and blood pressure regulation. Given PVAT\u2019s critical role in vascular function, this study aimed to investigate the effects of chronic copper overload on the secretory function of mesenteric PVAT, focusing on its vasoregulatory role. Methods: In the first phase, 8-week-old male Wistar rats were assigned to two groups, namely control (saline, i.p.) or copper (25.72 \u00b5g\/kg\/day Cu, i.p., for 30 days), corresponding to twice the recommended daily dose of copper. In the second phase, rats were divided into four groups: control (saline, i.p., water by gavage), copper (Cu, i.p., water by gavage), losartan (saline, i.p., 10 mg\/kg\/day losartan by gavage), or copper + losartan (Cu, i.p., 10 mg\/kg\/day losartan by gavage). After euthanasia, mesenteric PVAT was collected for morphometric analysis, gene and protein expression of adipokines, inflammatory molecules, and the renin\u2013angiotensin system. Serum was used for hormone and biochemical measurements. Results: In mesenteric PVAT, chronic copper overload increased adipocyte diameter and reduced lipolysis. It also elevated the secretion of TNF-\u03b1 and PAI-1 while decreasing IL-10 levels. Additionally, it upregulated the mRNA expression of MCP-1, F4\/80, CD86, TLR4, arginase-1, iNOS, ACE1, and AT1R, alongside an increase in serum angiotensin II levels. When copper treatment was combined with losartan, an AT1R antagonist, adipocyte hypertrophy; TNF-\u03b1 secretion; and the gene expression of TLR4, F4\/80, and arginase-1 were attenuated. Conclusions: Chronic exposure to double the recommended dose of Cu disrupts the secretory function of mesenteric PVAT, promoting inflammation and altering the local RAS. These effects appear to occur, at least in part, alongside the activation of the AT1R\u2013TLR4\u2013angiotensin II signaling pathway, triggering the upregulation of vasoregulatory inflammatory markers.<\/jats:p>","DOI":"10.3390\/nu17132082","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T09:08:44Z","timestamp":1750669724000},"page":"2082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chronic Copper Overload Triggers Inflammation in Mesenteric PVAT Alongside Changes in Renin\u2013Angiotensin System-Related Pathways"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6754-254X","authenticated-orcid":false,"given":"Nina Bruna de Souza","family":"Mawandji","sequence":"first","affiliation":[{"name":"Postgraduate Program in Physiology Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29043-900, ES, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayara Ariel da Silva","family":"Lisboa","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Nutrition and Health, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29043-900, ES, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8141-5880","authenticated-orcid":false,"given":"Karoline Neumann","family":"Gomes","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Physiology Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29043-900, ES, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2377-2504","authenticated-orcid":false,"given":"J\u00falia Martins","family":"Vieira","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Physiology Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29043-900, ES, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-8278","authenticated-orcid":false,"given":"Jussara de Jesus","family":"Sim\u00e3o","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of S\u00e3o Paulo, Sao Paulo 04039-032, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5847-8080","authenticated-orcid":false,"given":"Maria Isabel","family":"Alonso-Vale","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of S\u00e3o Paulo, Sao Paulo 04039-032, SP, Brazil"},{"name":"Postgraduate Program in Nutrition, Paulista School of Medicine, Federal University of S\u00e3o Paulo, Sao Paulo 04039-032, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3433-4925","authenticated-orcid":false,"given":"Karolini Zuqui","family":"Nunes","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Physiology Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29043-900, ES, Brazil"},{"name":"Postgraduate Program in Nutrition and Health, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29043-900, ES, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalton Valentim","family":"Vassallo","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Physiology Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29043-900, ES, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1244-5667","authenticated-orcid":false,"given":"Andressa","family":"Bolsoni-Lopes","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Physiology Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29043-900, ES, Brazil"},{"name":"Postgraduate Program in Nutrition and Health, Health Sciences Center, Federal University of Espirito Santo, Vitoria 29043-900, ES, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yang, L., Chen, X., Cheng, H., and Zhang, L. 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