{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T13:00:35Z","timestamp":1781701235618,"version":"3.54.5"},"reference-count":41,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000332","name":"Royal Society of Edinburgh","doi-asserted-by":"publisher","award":["2776"],"award-info":[{"award-number":["2776"]}],"id":[{"id":"10.13039\/501100000332","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Vascular endothelial growth factor receptor (VEGFR) inhibitors are effective antiangiogenic agents used in cancer therapy. However, they are associated with cardiovascular disease, including hypertension and vascular dysfunction. The molecular mechanisms underlying these cardiovascular toxicities are unclear, but oxidative stress might be important. Here we investigated the potential role of redox\u2010sensitive poly(ADP\u2010ribose) polymerase (PARP) and sirtuin 1 (SIRT1) in VEGFR inhibitor\u2010induced vascular injury. Molecular studies were performed in axitinib (VEGFR inhibitor)\u2010treated human aortic endothelial cells, and vascular studies were undertaken in isolated intact vessels from mice. Axitinib increased reactive oxygen species production and PARP activation. This was prevented by tiron (antioxidant) and olaparib (PARP inhibitor). Phosphorylation of endothelial nitric oxide synthase at Thr\n                    <jats:sup>495<\/jats:sup>\n                    (inhibitory site) was increased and activity of SIRT1 was reduced following axitinib treatment. This was accompanied by increased p53 acetylation; these effects were mitigated by olaparib or the SIRT1 activator SRT1720. VEGFR inhibition increased expression and secretion of pro\u2010inflammatory markers (MCP\u20101 and interleukin\u20106) and adhesion molecules (VCAM\u20101 and ICAM\u20101) and promoted THP\u20101 monocyte adhesion to human aortic endothelial cells, effects that were attenuated by PARP inhibition or SIRT1 activation. In isolated arteries, axitinib enhanced contractile responses to U46619 and endothelin\u20101 while impairing ACh\u2010induced relaxation. Co\u2010treatment with olaparib or SRT1720 restored vascular responses and endothelial nitric oxide synthase phosphorylation. In conclusion, inhibition of VEGFR signalling induces oxidative stress and PARP activation, leading to SIRT1 downregulation, endothelial dysfunction and vascular inflammation. Targeting PARP activation or enhancing SIRT1 activity might represent promising strategies to mitigate VEGF inhibitor\u2010induced vascular complications.\n                  <\/jats:p>","DOI":"10.1113\/ep093180","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T12:21:31Z","timestamp":1781698891000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["VEGF inhibitor\u2010induced vascular dysfunction involves redox\u2010sensitive PARP activation and SIRT1 disruption"],"prefix":"10.1113","author":[{"given":"Karla B.","family":"Neves","sequence":"first","affiliation":[{"name":"Strathclyde Institute of Pharmacy &amp; Biomedical Sciences University of Strathclyde  Glasgow UK"},{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rheure","family":"Alves\u2010Lopes","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow  Glasgow UK"},{"name":"School of Medicine, Medical Sciences and Nutrition University of Aberdeen  Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augusto C.","family":"Montezano","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow  Glasgow UK"},{"name":"Research Institute of the McGill University Health Centre  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0670-0887","authenticated-orcid":false,"given":"Rhian M.","family":"Touyz","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow  Glasgow UK"},{"name":"Research Institute of the McGill University Health Centre  Montreal Quebec Canada"},{"name":"Department of Medicine and Department of Family Medicine McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"issue":"2","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.critrevonc.2015.05.004","article-title":"Cardiac and vascular toxicities of angiogenesis inhibitors: The other side of the coin","volume":"96","author":"Alameddine R. 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H.","year":"2021","journal-title":"Cancer Treatment and Research Communications"},{"issue":"9","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1097\/HJH.0000000000003478","article-title":"Vasoprotective effects of NOX4 are mediated via polymerase and transient receptor potential melastatin 2 cation channels in endothelial cells","volume":"41","author":"Alves\u2010Lopes R.","year":"2023","journal-title":"Journal of Hypertension"},{"issue":"1","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1161\/HYPERTENSIONAHA.119.13861","article-title":"Crosstalk between vascular redox and calcium signaling in hypertension involves TRPM2 (transient receptor potential melastatin 2) cation channel","volume":"75","author":"Alves\u2010Lopes R.","year":"2020","journal-title":"Hypertension"},{"issue":"5","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1161\/HYPERTENSIONAHA.118.11830","article-title":"PARP\u20101 (Poly[ADP\u2010Ribose] polymerase\u20101)","volume":"72","author":"Alves\u2010Lopes R.","year":"2018","journal-title":"Hypertension"},{"issue":"2","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.tcm.2013.07.001","article-title":"Loss\u2010of\u2010SIRT1 function during vascular ageing: Hyperphosphorylation mediated by cyclin\u2010dependent kinase 5","volume":"24","author":"Bai B.","year":"2014","journal-title":"Trends in Cardiovascular Medicine"},{"issue":"4","key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.cmet.2011.03.013","article-title":"PARP\u20102 regulates SIRT1 expression and whole\u2010body energy expenditure","volume":"13","author":"Bai P.","year":"2011","journal-title":"Cell metabolism"},{"issue":"4","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.cmet.2011.03.004","article-title":"PARP\u20101 inhibition increases mitochondrial metabolism through SIRT1 activation","volume":"13","author":"Bai P.","year":"2011","journal-title":"Cell metabolism"},{"issue":"10","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/hr.2013.48","article-title":"SIRT1, heme oxygenase\u20101 and NO\u2010mediated vasodilation in a human model of endogenous angiotensin II type 1 receptor antagonism: Implications for hypertension","volume":"36","author":"Davis P. A.","year":"2013","journal-title":"Hypertension Research"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","DOI":"10.4061\/2011\/816897","article-title":"Vascular endothelial growth factor inhibitor\u2010induced hypertension: Basics for primary care providers","volume":"2011","author":"Escalante C. P.","year":"2011","journal-title":"Cardiology Research and Practice"},{"issue":"7","key":"e_1_2_10_12_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0101145","article-title":"Systematic review of the risk of adverse outcomes associated with vascular endothelial growth factor inhibitors for the treatment of cancer","volume":"9","author":"Faruque L. 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Y.","year":"2024","journal-title":"Journal of Clinical Medicine"},{"issue":"8","key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1016\/j.bbamcr.2013.04.005","article-title":"Poly(ADP\u2010ribose) polymerase\u20101\u2010induced NAD(+) depletion promotes nuclear factor\u2010kappaB transcriptional activity by preventing p65 de\u2010acetylation","volume":"1833","author":"Kauppinen T. M.","year":"2013","journal-title":"Biochimica Et Biophysica Acta"},{"issue":"24","key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"4758","DOI":"10.1016\/j.molcel.2024.10.024","article-title":"PARP enzyme de novo synthesis of protein\u2010free poly(ADP\u2010ribose)","volume":"84","author":"Langelier M. 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C.","year":"2023","journal-title":"Hypertension"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopha.2024.117585","article-title":"Physiological and tumor\u2010associated angiogenesis: Key factors and therapy targeting VEGF\/VEGFR pathway","volume":"180","author":"Lorenc P.","year":"2024","journal-title":"Biomedicine & Pharmacotherapy"},{"issue":"1","key":"e_1_2_10_19_1","first-page":"6","article-title":"SIRT1\/PARP1 crosstalk: Connecting DNA damage and metabolism","volume":"4","author":"Luna A.","year":"2013","journal-title":"Genome Integrity"},{"issue":"23","key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1042\/BCJ20200525","article-title":"PARP\u20101 activation after oxidative insult promotes energy stress\u2010dependent phosphorylation of YAP1 and reduces cell viability","volume":"477","author":"Mart\u00edn\u2010Guerrero S. M.","year":"2020","journal-title":"Biochemical Journal"},{"issue":"37","key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"14855","DOI":"10.1073\/pnas.0704329104","article-title":"SIRT1 promotes endothelium\u2010dependent vascular relaxation by activating endothelial nitric oxide synthase","volume":"104","author":"Mattagajasingh I.","year":"2007","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"2","key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"366","DOI":"10.3390\/life13020366","article-title":"Cardiovascular toxicity induced by vascular endothelial growth factor inhibitors","volume":"13","author":"Mihalcea D.","year":"2023","journal-title":"Life"},{"issue":"7170","key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/nature06261","article-title":"Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes","volume":"450","author":"Milne J. 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