{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T12:14:59Z","timestamp":1771071299081,"version":"3.50.1"},"reference-count":88,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Vasoinhibin is a potent antiangiogenic protein that blocks the activation of endothelial nitric oxide synthase (eNOS) in response to vascular endothelial growth factor, bradykinin, and acetylcholine (ACh). In this regard, VIAN\u2010c4551, a new synthetic vasoinhibin analog, has therapeutic potential for targeting angiogenesis in oncology and ophthalmology. Given that cardiovascular actions are common complications of antiangiogenic drugs and eNOS inhibitors, this multidisciplinary study investigated the cardiovascular safety of VIAN\u2010c4551. Administered acutely, VIAN\u2010c4551 inhibited ACh\u2010induced eNOS phosphorylation\/activation in cultured endothelial cells and in lung tissue treated in vivo, as well as the ACh\u2010induced relaxation of rat aortic segments. However, daily intravenous (i.v.) injections of VIAN\u2010c4551 (1 or 3\u2009mg\u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) for 5 days failed to significantly modify the vasodepressor responses to ACh and the baseline values of blood pressure in anesthetized rats (intact, vagotomized, or pithed). Furthermore, daily i.v. injections of 1\u2009mg\u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    VIAN\u2010c4551 (for 5 days) did not alter: (i) blood pressure or heart rate values in awake rats; (ii) cardiac autonomic and histological outcomes in anesthetized animals; or (iii) inflammatory (tumor necrosis factor\u2010\u03b1 [TNF\u2010\u03b1] and interleukin\u20106 [IL\u20106]) and apoptotic (caspase\u20103) markers. Although VIAN\u2010c4551 inhibited ACh\u2010induced eNOS activation in vitro and in vivo and vasorelaxation in\n                    <jats:italic>ex vivo<\/jats:italic>\n                    assays, in vivo experiments consistently showed no significant cardiovascular effects produced by this synthetic peptide. Thus, VIAN\u2010c4551 appears to be cardiovascularly safe for targeting angiogenesis\u2010related diseases.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70177","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T07:00:23Z","timestamp":1759820423000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiovascular Safety of VIAN\u2010c4551, an Antiangiogenic Peptide Derived From Vasoinhibin"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0826-2932","authenticated-orcid":false,"given":"Miguel A.","family":"Garc\u00eda\u2010Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Instituto de Neurobiolog\u00eda Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Quer\u00e9taro, Qro Mexico"},{"name":"Instituto de Fisiolog\u00eda Benem\u00e9rita Universidad Aut\u00f3noma de Puebla (BUAP) Puebla, Pue Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5176-5466","authenticated-orcid":false,"given":"Alejandro D.","family":"Miguel\u2010Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Departamento de Farmacobiolog\u00eda Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, Unidad Sede Sur Mexico City Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6472-1419","authenticated-orcid":false,"given":"Abimael","family":"Gonz\u00e1lez\u2010Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Quer\u00e9taro, Qro Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5579-1004","authenticated-orcid":false,"given":"Magdalena","family":"Zamora","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Quer\u00e9taro, Qro Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6911-0515","authenticated-orcid":false,"given":"Elva","family":"Ad\u00e1n\u2010Castro","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Quer\u00e9taro, Qro Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6887-2358","authenticated-orcid":false,"given":"Xarubet","family":"Ru\u00edz\u2010Herrera","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Quer\u00e9taro, Qro Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6049-2600","authenticated-orcid":false,"given":"Mar\u00eda A.","family":"Carbajo\u2010Mata","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Quer\u00e9taro, Qro Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1989-8645","authenticated-orcid":false,"given":"Jakob","family":"Triebel","sequence":"additional","affiliation":[{"name":"Laboratory Medicine and Transfusion Medicine, Institute for Clinical Chemistry, Nuremberg General Hospital Paracelsus Medical University Nuremberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8600-5544","authenticated-orcid":false,"given":"Thomas","family":"Bertsch","sequence":"additional","affiliation":[{"name":"Laboratory Medicine and Transfusion Medicine, Institute for Clinical Chemistry, Nuremberg General Hospital Paracelsus Medical University Nuremberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4119-3833","authenticated-orcid":false,"given":"Jos\u00e9 G.","family":"Lopez\u2010Lopez","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia Benem\u00e9rita Universidad Aut\u00f3noma de Puebla (BUAP) Puebla, Pue Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4309-3476","authenticated-orcid":false,"given":"Gonzalo","family":"Mart\u00ednez de la Escalera","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Quer\u00e9taro, Qro Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8429-1914","authenticated-orcid":false,"given":"Juan Pablo","family":"Robles","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Quer\u00e9taro, Qro Mexico"},{"name":"VIAN Therapeutics San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7670-6718","authenticated-orcid":false,"given":"Carmen","family":"Clapp","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Quer\u00e9taro, Qro Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4117-1343","authenticated-orcid":false,"given":"Carlos M.","family":"Villal\u00f3n","sequence":"additional","affiliation":[{"name":"Departamento de Farmacobiolog\u00eda Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, Unidad Sede Sur Mexico City Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-12331-w"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-010-0815-4"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13621-8"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29877"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13799"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00789443"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.54"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115849"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00122.2003"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0603-653"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.114198"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1159\/000158978"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2006.08.002"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-12114-7_4"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.477"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.18.13183"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00379.2022"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.112.196774"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics13132166"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20200305"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-020-00569-1"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.129973"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.12.022"},{"key":"e_1_2_10_25_1","first-page":"498","volume-title":"Vascular Function: Hemodynamics. Quantitative Human Physiology: An Introduction","author":"Feher J. J.","year":"2012"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0736-0266(02)00235-8"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25126661"},{"issue":"6","key":"e_1_2_10_28_1","first-page":"2291","article-title":"Vasoinhibins Prevent Retinal Vasopermeability Associated With Diabetic Retinopathy ni Rats via Protein Phosphatase 2A\u2010dependent eNOS Inactivation","volume":"118","author":"Garc\u00eda C.","year":"2008","journal-title":"Journal of Clinical Investigation"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-0647"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700662"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-018-0869-8"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0316983"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.5114\/ait.2022.121003"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq127"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.579603"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.12.036"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2005.031252"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2007.040055"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/377239a0"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2020.1787986"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.40725"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1964.19.2.360"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom14010103"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-323-91391-1.00034-0"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13096"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.22.1.40"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1159\/000516939"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.110.168120"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1385\/ENDO:20:1-2:155"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.122.317759"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.2170\/jjphysiol.53.193"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pep.2019.04.011"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2015.03.018"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2017.00004"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300294"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-199701000-00014"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaf023"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-2427"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-020-0432-5"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0255561"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/327524a0"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0001-37652010000200019"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0316983"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2015.73"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2008.360"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1111\/1440-1681.12949"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2010.09.007"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqad185"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-021-09800-x"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920111796117300"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2024.08.062"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.30.1.64"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.26.4.691"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1097\/00041552-199901000-00011"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1364758"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00168962"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0b013e31820b7dc9"},{"key":"e_1_2_10_78_1","first-page":"101","article-title":"Cardiovascular Responses to Acetylcholine: Effects of Pentobarbital and Autonomic Blocking Agents. Conditional Reflex: A Pavlovian","volume":"6","author":"Tettelbaum H. A.","year":"1971","journal-title":"Journal of Research & Therapy"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.2174\/1573403X16999201231203854"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.117.08856"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00256.2015"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.994898"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00421-013-2639-2"},{"key":"e_1_2_10_84_1","doi-asserted-by":"publisher","DOI":"10.33549\/physiolres.930195"},{"key":"e_1_2_10_85_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-007-0179-1"},{"key":"e_1_2_10_86_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1345996"},{"key":"e_1_2_10_87_1","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2016.241"},{"key":"e_1_2_10_88_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI33338"},{"key":"e_1_2_10_89_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S99376"}],"container-title":["Drug Development Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.70177","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ddr.70177","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.70177","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T11:52:11Z","timestamp":1771069931000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/ddr.70177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":88,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1002\/ddr.70177"],"URL":"https:\/\/doi.org\/10.1002\/ddr.70177","archive":["Portico"],"relation":{},"ISSN":["0272-4391","1098-2299"],"issn-type":[{"value":"0272-4391","type":"print"},{"value":"1098-2299","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]},"assertion":[{"value":"2025-04-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70177"}}