{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:21:47Z","timestamp":1780449707220,"version":"3.54.1"},"reference-count":54,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2014,8,13]],"date-time":"2014-08-13T00:00:00Z","timestamp":1407888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Melatonin, a naturally-occurring hormone, possesses antioxidant properties  and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact  of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs) to hypoxia and further investigate whether ERK\/Rac1 signaling is involved  in this process. Here, we found that melatonin inhibited hypoxia-stimulated  hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) expression and cell migration in a dose-dependent manner. Mechanistically, melatonin inhibited Rac1 activation and suppressed the  co-localized Rac1 and F-actin on the membrane of HUVECs under hypoxic condition.  In addition, the blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1-T17N suppressed HIF-1\u03b1 expression and cell migration in response to hypoxia, as well, but constitutive activation of Rac1 mutant Rac1-V12 restored HIF-1\u03b1 expression, preventing the inhibition of melatonin on cell migration. Furthermore, the  anti-Rac1 effect of melatonin in HUVECs appeared to be associated with its inhibition of ERK phosphorylation, but not that of the PI3k\/Akt signaling pathway. Taken together, our work indicates that melatonin exerts an anti-migratory effect on hypoxic HUVECs by blocking ERK\/Rac1 activation and subsequent HIF-1\u03b1 upregulation.<\/jats:p>","DOI":"10.3390\/ijms150814102","type":"journal-article","created":{"date-parts":[[2014,8,13]],"date-time":"2014-08-13T12:15:41Z","timestamp":1407932141000},"page":"14102-14121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Melatonin Suppresses Hypoxia-Induced Migration of HUVECs via Inhibition of ERK\/Rac1 Activation"],"prefix":"10.3390","volume":"15","author":[{"given":"Ling","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Cardiology, the Third Affiliated Hospital of Soochow University,  Changzhou 213003, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianchao","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luo","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Dong","sequence":"additional","affiliation":[{"name":"Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, Nanjing Medical University, Nanjing 210029, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijue","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Third Affiliated Hospital of Soochow University,  Changzhou 213003, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University,  Changzhou 213003, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University,  Changzhou 213003, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/jpi.12067","article-title":"Melatonin ameliorates endothelial dysfunction, vascular inflammation, and systemic hypertension in rats with chronic intermittent hypoxia","volume":"55","author":"Hung","year":"2013","journal-title":"J. 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