{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:31:15Z","timestamp":1792042275744,"version":"4.4.0"},"reference-count":61,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","license":[{"start":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T00:00:00Z","timestamp":1716508800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,5,24]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Neutrophil extracellular traps (NETs) are composed of DNA, enzymes, and citrullinated histones that are expelled by neutrophils in the process of NETosis. NETs accumulate in the aorta and kidneys in hypertension. PAD4 (protein-arginine deiminase-4) is a calcium-dependent enzyme that is essential for NETosis. TRPV4 (transient receptor potential cation channel subfamily V member 4) is a mechanosensitive calcium channel expressed in neutrophils. Thus, we hypothesize that NETosis contributes to hypertension via NET-mediated endothelial cell (EC) dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      NETosis-deficient\n                      <jats:italic toggle=\"yes\">Padi4<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice were treated with Ang II (angiotensin II). Blood pressure was measured by radiotelemetry, and vascular reactivity was measured with wire myography. Neutrophils were cultured with or without ECs and exposed to normotensive or hypertensive uniaxial stretch. NETosis was measured by flow cytometry. ECs were treated with citrullinated histone H3, and gene expression was measured by quantitative reverse transcription PCR. Aortic rings were incubated with citrullinated histone H3, and wire myography was performed to evaluate EC function. Neutrophils were treated with the TRPV4 agonist GSK1016790A. Calcium influx was measured using Fluo-4 dye, and NETosis was measured by immunofluorescence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Padi4<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice exhibited attenuated hypertension, reduced aortic inflammation, and improved EC-dependent vascular relaxation in response to Ang II. Coculture of neutrophils with ECs and exposure to hypertensive uniaxial stretch increased NETosis and accumulation of neutrophil citrullinated histone H3. Histone H3 and citrullinated histone H3 exposure attenuates EC-dependent vascular relaxation. Treatment of neutrophils with the TRPV4 agonist GSK1016790A increases intracellular calcium and NETosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These observations identify a role of NETosis in the pathogenesis of hypertension. Moreover, they define an important role of EC stretch and TRPV4 as initiators of NETosis. Finally, they define a role of citrullinated histones as drivers of EC dysfunction in hypertension.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.123.323897","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T05:00:32Z","timestamp":1714107632000},"page":"1483-1494","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":61,"title":["NETosis Drives Blood Pressure Elevation and Vascular Dysfunction in Hypertension"],"prefix":"10.1161","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9752-4219","authenticated-orcid":true,"given":"Jaya","family":"Krishnan","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine (J.K., A.K., T.A., N.d.l.V., D.M.P.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1823-5751","authenticated-orcid":true,"given":"Elizabeth M.","family":"Hennen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, TN (E.M.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingfang","family":"Ao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology (M.A.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8580-9359","authenticated-orcid":true,"given":"Annet","family":"Kirabo","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine (J.K., A.K., T.A., N.d.l.V., D.M.P.), Vanderbilt University Medical Center, Nashville, TN."},{"name":"Vanderbilt Center for Immunobiology (A.K.)."},{"name":"Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN (A.K.)."},{"name":"Vanderbilt Institute for Global Health, Nashville, TN (A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4545-9598","authenticated-orcid":true,"given":"Taseer","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine (J.K., A.K., T.A., N.d.l.V., D.M.P.), Vanderbilt University Medical Center, Nashville, TN."},{"name":"Department of Pharmacology, College of Pharmacy, University of Sargodha, Sargodha, Pakistan (T.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7229-9601","authenticated-orcid":true,"given":"N\u00e9stor","family":"de la Visitaci\u00f3n","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine (J.K., A.K., T.A., N.d.l.V., D.M.P.), Vanderbilt University Medical Center, Nashville, TN."},{"name":"Division of Cardiovascular Medicine, Department of Medicine (D.M.P.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Patrick","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine (J.K., A.K., T.A., N.d.l.V., D.M.P.), Vanderbilt University Medical Center, Nashville, TN."},{"name":"Department of Veterans Affairs, Nashville, TN (D.M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.161.12.1501"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.032582"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.04012"},{"key":"e_1_3_3_5_2","first-page":"1","article-title":"Hypertension prevalence among adults aged 18 and over: United states, 2017-2018.","volume":"1","author":"Ostchega Y","year":"2020","unstructured":"Ostchega, Y, Fryar, CD, Nwankwo, T, Nguyen, DT. Hypertension prevalence among adults aged 18 and over: United states, 2017-2018. NCHS Data Brief. 2020;1:1\u20138.","journal-title":"NCHS Data Brief"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.14545"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.122.19222"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2020.01.013"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20171773"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00113"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12872-023-03304-w"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41440-019-0245-3"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.122.19305"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1134\/S0006297920100065"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.312494"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.4172\/2155-9899.1000139"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.148668"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0000000000003231"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.113.301627"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1301059110"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.056414"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.118.311150"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.07.069"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02957"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0097088"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1211601"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb799"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/jleuko\/qiad063"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0225OC"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI74084"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.315767"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.04975"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.04147"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142735.im0320s110"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy112"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.136678"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-019-0195-8"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab330"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201500088R"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa8064"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202048878"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.319643"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.320818"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-021-01128-7"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.116.07237"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070657"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI87425"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2019.06.008"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-16342-0"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0702593"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1997.4361"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2021.120715"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1159\/000339151"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1186\/2050-7771-2-1"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1170"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2015.10.012"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00655.2018"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3RU0620-375R"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-04-457671"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2847"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32225-6"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9040915"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.123.323897","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T16:04:06Z","timestamp":1748534646000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.123.323897"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,24]]},"references-count":61,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,5,24]]}},"alternative-id":["10.1161\/CIRCRESAHA.123.323897"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.123.323897","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,24]]},"assertion":[{"value":"2023-10-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-18","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}