{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T22:14:22Z","timestamp":1767046462807,"version":"3.37.3"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG GE905\/19-1 and 2, GE905\/24-1"],"award-info":[{"award-number":["DFG GE905\/19-1 and 2, GE905\/24-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Martin-Luther-Universit\u00e4t Halle-Wittenberg"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vascular EGF receptors (EGFR) influence function and structure of arterial vessels. In genetic mouse models we described the role of vascular smooth muscle (VSMC) EGFR for proper physiological function and structure as well as for pathophysiological alterations by obesity or angiotensin II. As the importance of endothelial (EC) EGFR in vivo is unknown, we analyzed the impact of EC-EGFR knockout in a conditional mouse model on vascular and renal function under control condition as well as in obesity and in comparison to VSMC-KO. Heart and lung weight, blood pressure and aortic transcriptome (determined by RNA-seq) were not affected by EC-EGFR-KO. Aortic reactivity to \u03b11-adrenergic stimulation was not affected by EC-EGFR-KO contrary to VSMC-EGFR-KO. Endothelial-induced relaxation was reduced in abdominal aorta of EC-EGFR-KO animals, whereas it was enhanced in VSMC-EGFR-KO animals. Mesenteric arteries of EC-EGFR-KO animals showed enhanced sensitivity to \u03b11-adrenergic stimulation, whereas endothelial-induced relaxation and vessel morphology were not affected. Renal weight, histomorphology, function (albumin excretion, serum creatinine, fractional water excretion) or transcriptome were not affected by EC-EGFR-KO, likewise in VSMC-EGFR-KO. High fat diet (HFD) over 18\u00a0weeks induced arterial wall thickening, renal weight increase, creatininemia, renal and aortic transcriptome alterations with a similar pattern in EC-EGFR-WT and EC-EGFR-KO animals by contrast to the previously reported impact of VSMC-EGFR-KO. HFD induced endothelial dysfunction in abdominal aortae of EC-EGFR-WT, which was not additive to the EC-EGFR-KO-induced endothelial dysfunction. As shown before, VSMC-EGFR-KO prevented HFD-induced endothelial dysfunction. HFD-induced albuminuria was less pronounced in EC-EGFR-KO animals and abrogated in VSMC-EGFR-KO animals. Our results indicate that EC-EGFR, in comparison to VSMC-EGFR, is of minor and opposite importance for basal renovascular function as well as for high fat diet-induced vascular remodeling and renal end organ damage.<\/jats:p>","DOI":"10.1038\/s41598-021-86587-3","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T10:03:51Z","timestamp":1617185031000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Endothelial epidermal growth factor receptor is of minor importance for vascular and renal function and obesity-induced dysfunction in mice"],"prefix":"10.1038","volume":"11","author":[{"given":"Barbara","family":"Schreier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Stern","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginie","family":"Dubourg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Nolze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sindy","family":"Rabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sigrid","family":"Mildenberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Wickenhauser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1581-8767","authenticated-orcid":false,"given":"Michael","family":"Gekle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,31]]},"reference":[{"key":"86587_CR1","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.ceb.2007.02.008","volume":"19","author":"EM Bublil","year":"2007","unstructured":"Bublil, E. M. & Yarden, Y. The EGF receptor family: Spearheading a merger of signaling and therapeutics. Curr. Opin. Cell Biol. 19, 124\u2013134 (2007).","journal-title":"Curr. Opin. Cell Biol."},{"key":"86587_CR2","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1161\/HYPERTENSIONAHA.112.196543","volume":"61","author":"B Schreier","year":"2013","unstructured":"Schreier, B. et al. Loss of epidermal growth factor receptor in vascular smooth muscle cells and cardiomyocytes causes arterial hypotension and cardiac hypertrophy. Hypertension 61, 333\u2013340 (2013).","journal-title":"Hypertension"},{"key":"86587_CR3","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1146\/annurev-pharmtox-070115-095427","volume":"56","author":"SJ Forrester","year":"2016","unstructured":"Forrester, S. J. et al. Epidermal growth factor receptor transactivation: Mechanisms, pathophysiology, and potential therapies in the cardiovascular system. Annu. Rev. Pharmacol. Toxicol. 56, 627\u2013653 (2016).","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"86587_CR4","doi-asserted-by":"publisher","first-page":"e12996","DOI":"10.1111\/apha.12996","volume":"222","author":"B Schreier","year":"2017","unstructured":"Schreier, B. et al. Deletion of the EGF receptor in vascular smooth muscle cells prevents chronic angiotensin-II-induced arterial wall stiffening and media thickening. Acta Physiol. 222, e12996 (2017).","journal-title":"Acta Physiol."},{"key":"86587_CR5","doi-asserted-by":"publisher","first-page":"2218","DOI":"10.1007\/s00125-020-05187-4","volume":"63","author":"C Stern","year":"2020","unstructured":"Stern, C. et al. Knockout of vascular smooth muscle EGF receptor in a mouse model prevents obesity-induced vascular dysfunction and renal damage in vivo. Diabetologia 63, 2218\u20132234 (2020).","journal-title":"Diabetologia"},{"key":"86587_CR6","doi-asserted-by":"publisher","first-page":"20597","DOI":"10.3390\/ijms141020597","volume":"14","author":"N Makki","year":"2013","unstructured":"Makki, N., Thiel, K. W. & Miller, F. J. Jr. The epidermal growth factor receptor and its ligands in cardiovascular disease. Int. J. Mol. Sci. 14, 20597\u201320613 (2013).","journal-title":"Int. J. Mol. Sci."},{"key":"86587_CR7","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1097\/01.mnh.0000441152.62943.29","volume":"23","author":"B Schreier","year":"2014","unstructured":"Schreier, B., Gekle, M. & Grossmann, C. Role of epidermal growth factor receptor in vascular structure and function. Curr. Opin. Nephrol. Hypertens. 23, 113\u2013121 (2014).","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"86587_CR8","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.2337\/db07-0739","volume":"57","author":"S Belmadani","year":"2008","unstructured":"Belmadani, S., Palen, D. I., Gonzalez-Villalobos, R. A., Boulares, H. A. & Matrougui, K. Elevated epidermal growth factor receptor phosphorylation induces resistance artery dysfunction in diabetic db\/db mice. Diabetes 57, 1629\u20131637 (2008).","journal-title":"Diabetes"},{"key":"86587_CR9","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1038\/sj.bjp.0706238","volume":"145","author":"IF Benter","year":"2005","unstructured":"Benter, I. F., Yousif, M. H. M., Griffiths, S. M., Benboubetra, M. & Akhtar, S. Epidermal growth factor receptor tyrosine kinase-mediated signalling contributes to diabetes-induced vascular dysfunction in the mesenteric bed. Br. J. Pharmacol. 145, 829\u2013836 (2005).","journal-title":"Br. J. Pharmacol."},{"key":"86587_CR10","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.vph.2009.06.008","volume":"51","author":"IF Benter","year":"2009","unstructured":"Benter, I. F. et al. Early inhibition of EGFR signaling prevents diabetes-induced up-regulation of multiple gene pathways in the mesenteric vasculature. Vascul. Pharmacol. 51, 236\u2013245 (2009).","journal-title":"Vascul. Pharmacol."},{"key":"86587_CR11","doi-asserted-by":"publisher","first-page":"506","DOI":"10.3109\/1061186X.2015.1057150","volume":"23","author":"IF Benter","year":"2015","unstructured":"Benter, I. F. et al. The dual targeting of EGFR and ErbB2 with the inhibitor Lapatinib corrects high glucose-induced apoptosis and vascular dysfunction by opposing multiple diabetes-induced signaling changes. J. Drug Target 23, 506\u2013518 (2015).","journal-title":"J. Drug Target"},{"key":"86587_CR12","doi-asserted-by":"publisher","first-page":"21603","DOI":"10.1074\/jbc.M115.651604","volume":"290","author":"R Li","year":"2015","unstructured":"Li, R. et al. High glucose up-regulates ADAM17 through HIF-1a in mesangial cells. J. Biol. Chem. 290, 21603\u201321614 (2015).","journal-title":"J. Biol. Chem."},{"key":"86587_CR13","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1161\/HYPERTENSIONAHA.112.197038","volume":"60","author":"T Kobayashi","year":"2012","unstructured":"Kobayashi, T. & Eguchi, S. The epidermal growth factor receptor: a missing link between endoplasmic reticulum stress and diabetic complications?. Hypertension 60, 20\u201321 (2012).","journal-title":"Hypertension"},{"key":"86587_CR14","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1158\/0008-5472.CAN-05-3387","volume":"66","author":"DN Amin","year":"2006","unstructured":"Amin, D. N., Hida, K., Bielenberg, D. R. & Klagsbrun, M. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res. 66, 2173 (2006).","journal-title":"Cancer Res."},{"key":"86587_CR15","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1042\/CS20150503","volume":"130","author":"B Schreier","year":"2016","unstructured":"Schreier, B. et al. Consequences of postnatal vascular smooth muscle EGF-receptor deletion on acute angiotensin II action. Clin. Sci. 130, 19\u201333 (2016).","journal-title":"Clin. Sci."},{"key":"86587_CR16","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1006\/dbio.2000.0106","volume":"230","author":"YY Kisanuki","year":"2001","unstructured":"Kisanuki, Y. Y. et al. Tie2-Cre transgenic mice: A new model for endothelial cell-lineage analysis in vivo. Dev. Biol. 230, 230\u2013242 (2001).","journal-title":"Dev. Biol."},{"key":"86587_CR17","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1161\/01.RES.41.1.19","volume":"41","author":"MJ Mulvany","year":"1977","unstructured":"Mulvany, M. J. & Halpern, W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ. Res. 41, 19\u201326 (1977).","journal-title":"Circ. Res."},{"key":"86587_CR18","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1161\/HYPERTENSIONAHA.108.110197","volume":"52","author":"Y Wang","year":"2008","unstructured":"Wang, Y., Bab\u00ednkov\u00ed, D., Huang, J., Swain, G. M. & Wang, D. H. Deletion of transient receptor potential vanilloid type 1 receptors exaggerates renal damage in deoxycorticosterone acetate-salt hypertension. Hypertension 52, 264\u2013270 (2008).","journal-title":"Hypertension"},{"key":"86587_CR19","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/s00441-003-0731-3","volume":"313","author":"M Liang","year":"2003","unstructured":"Liang, M., Ekblad, E., Lydrup, M. L. & Nilsson, B. O. Combined lack of estrogen receptors alpha and beta affects vascular iNOS protein expression. Cell Tissue Res. 313, 63\u201370 (2003).","journal-title":"Cell Tissue Res."},{"key":"86587_CR20","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1161\/ATVBAHA.111.223537","volume":"31","author":"B Schreier","year":"2011","unstructured":"Schreier, B. et al. Consequences of epidermal growth factor receptor (ErbB1) loss for vascular smooth muscle cells from mice with targeted deletion of ErbB1. Arterioscler. Thromb. Vasc. Biol. 31, 1643\u20131652 (2011).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"86587_CR21","doi-asserted-by":"publisher","first-page":"R36","DOI":"10.1186\/gb-2013-14-4-r36","volume":"14","author":"D Kim","year":"2013","unstructured":"Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36 (2013).","journal-title":"Genome Biol."},{"key":"86587_CR22","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","volume":"30","author":"Y Liao","year":"2013","unstructured":"Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923\u2013930 (2013).","journal-title":"Bioinformatics"},{"key":"86587_CR23","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1038\/nprot.2009.97","volume":"4","author":"S Durinck","year":"2009","unstructured":"Durinck, S., Spellman, P. T., Birney, E. & Huber, W. Mapping identifiers for the integration of genomic datasets with the R\/Bioconductor package biomaRt. Nat. Protoc. 4, 1184\u20131191 (2009).","journal-title":"Nat. Protoc."},{"key":"86587_CR24","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2009","unstructured":"Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139\u2013140 (2009).","journal-title":"Bioinformatics"},{"key":"86587_CR25","doi-asserted-by":"publisher","first-page":"W83","DOI":"10.1093\/nar\/gkw199","volume":"44","author":"J Reimand","year":"2016","unstructured":"Reimand, J. et al. g:Profiler-a web server for functional interpretation of gene lists (2016 update). Nucleic Acids Res 44, W83\u2013W89 (2016).","journal-title":"Nucleic Acids Res"},{"key":"86587_CR26","doi-asserted-by":"publisher","first-page":"2241","DOI":"10.1007\/s00018-017-2731-6","volume":"75","author":"M Polovic","year":"2018","unstructured":"Polovic, M. et al. Identification of a novel lncRNA induced by the nephrotoxin ochratoxin A and expressed in human renal tumor tissue. Cell. Mol. Life Sci. 75, 2241\u20132256 (2018).","journal-title":"Cell. Mol. Life Sci."},{"key":"86587_CR27","doi-asserted-by":"publisher","first-page":"25","DOI":"10.2337\/db15-0982","volume":"65","author":"DA Fontaine","year":"2016","unstructured":"Fontaine, D. A. & Davis, D. B. Attention to background strain is essential for metabolic research: C57BL\/6 and the International Knockout Mouse Consortium. Diabetes 65, 25 (2016).","journal-title":"Diabetes"},{"key":"86587_CR28","doi-asserted-by":"publisher","first-page":"2550","DOI":"10.1161\/ATVBAHA.118.309669","volume":"38","author":"S Payne","year":"2018","unstructured":"Payne, S., De, V. S. & Neal, A. Endothelial-specific Cre mouse models. Arterioscler. Thromb. Vasc. Biol. 38, 2550\u20132561 (2018).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"86587_CR29","doi-asserted-by":"publisher","first-page":"R82","DOI":"10.1186\/gb-2013-14-7-r82","volume":"14","author":"MM Simon","year":"2013","unstructured":"Simon, M. M. et al. A comparative phenotypic and genomic analysis of C57BL\/6J and C57BL\/6N mouse strains. Genome Biol. 14, R82 (2013).","journal-title":"Genome Biol."},{"key":"86587_CR30","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1007\/s00360-014-0830-3","volume":"184","author":"K Moreth","year":"2014","unstructured":"Moreth, K. et al. High-throughput phenotypic assessment of cardiac physiology in four commonly used inbred mouse strains. J. Comp. Physiol. B 184, 763\u2013775 (2014).","journal-title":"J. Comp. Physiol. B"},{"key":"86587_CR31","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/s41598-018-36862-7","volume":"9","author":"E Kawashita","year":"2019","unstructured":"Kawashita, E., Ishihara, K., Nomoto, M., Taniguchi, M. & Akiba, S. A comparative analysis of hepatic pathological phenotypes in C57BL\/6J and C57BL\/6N mouse strains in non-alcoholic steatohepatitis models. Sci. Rep. 9, 204 (2019).","journal-title":"Sci. Rep."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86587-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86587-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86587-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T06:10:39Z","timestamp":1670047839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86587-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,31]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["86587"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-86587-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2021,3,31]]},"assertion":[{"value":"23 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7269"}}