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However, the role of NOX4 in resistance arteries and in perivascular adipose tissue is not well understood. We hypothesized that NOX4 is of functional importance in resistance arteries and perivascular adipose tissue under dyslipidemia conditions. We detected elevated NOX4 expression in murine and human vessels under dyslipidemia. Diminishing Nox4 under these conditions led to endothelial dysfunction in resistance arteries. The mesenteric arteries of Nox4\u2212\/\u2212\/Ldlr\u2212\/\u2212 mice revealed decreased eNos mRNA expression. Inhibition of eNOS in those vessels did not affect vascular function, while in Ldlr\u2212\/\u2212 mice endothelial function was significantly altered. Anticontractile properties of perivascular adipose tissue at resistance arteries were diminished in Nox4\u2212\/\u2212\/Ldlr\u2212\/\u2212 compared with Ldlr\u2212\/\u2212 mice. In addition, the presence of perivascular adipose tissue further worsened endothelial dysfunction in mesenteric arteries under dyslipidemia conditions. Perivascular adipose tissue from mesenteric arteries revealed a higher expression of markers of white adipocytes compared to markers of beige\/brown adipocytes. Among those white adipocyte markers, leptin was significantly less expressed in perivascular adipose tissue from Nox4\u2212\/\u2212\/Ldlr\u2212\/\u2212 mice compared with Ldlr\u2212\/\u2212 mice. Furthermore, in human perivascular adipose tissue with a profound pattern of white adipocyte marker genes, we detected a correlation of NOX4 and LEP expression. In addition, incubating arterial vessels with leptin induced nitrite release, indicating increased eNOS activity. In humans, a higher expression of leptin in perivascular adipose tissue correlated with eNOS expression in the corresponding left internal mammary artery. In conclusion, vascular function of resistance arteries was dependent on Nox4-derived H2O2, especially under dyslipidemia conditions. Perivascular adipose tissue of the mesenteric arteries with white adipose tissue characteristics further aggravated endothelial function through reduced leptin-eNOS signaling.<\/jats:p>","DOI":"10.3390\/antiox13050503","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T08:08:27Z","timestamp":1713859707000},"page":"503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Vascular Function of Resistance Arteries Depends on NADPH Oxidase 4 and Is Exacerbated by Perivascular Adipose Tissue"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8672-6640","authenticated-orcid":false,"given":"Patrick","family":"Diaba-Nuhoho","sequence":"first","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Mittag","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coy","family":"Brunssen","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9360-9736","authenticated-orcid":false,"given":"Henning","family":"Morawietz","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1214-1807","authenticated-orcid":false,"given":"Heike","family":"Brendel","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1210\/endrev\/bnab037","article-title":"A Modern Approach to Dyslipidemia","volume":"43","author":"Berberich","year":"2022","journal-title":"Endocr. 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