{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:06:31Z","timestamp":1790298391124,"version":"4.1.0"},"reference-count":65,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,5,21]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">The vasoconstrictor effects of angiotensin II via type 1 angiotensin II receptors in vascular smooth muscle cells are well established, but the direct effects of angiotensin II on vascular endothelial cells (VECs) in\u00a0vivo and the mechanisms how VECs may mitigate angiotensin II\u2013mediated vasoconstriction are not fully understood. The present study aimed to explore the molecular mechanisms and pathophysiological relevance of the direct actions of angiotensin II on VECs in kidney and brain microvessels in\u00a0vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Changes in VEC intracellular calcium ([Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>\n                        <jats:italic>i<\/jats:italic>\n                      <\/jats:sub>\n                      ) and nitric oxide (NO) production were visualized by intravital multiphoton microscopy of cadherin 5\u2013Salsa6f mice or the endothelial uptake of NO\u2010sensitive dye 4\u2010amino\u20105\u2010methylamino\u20102\u2032,7\u2032\u2010difluorofluorescein diacetate, respectively. Kidney fibrosis by unilateral ureteral obstruction and Ready\u2010to\u2010use adeno\u2010associated virus expressing Mouse Renin 1 gene (Ren1\u2010AAV) hypertension were used as disease models.\n                    <\/jats:p>\n                    <jats:p xml:lang=\"en\">\n                      Acute systemic angiotensin II injections triggered &gt;4\u2010fold increases in VEC [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>\n                        <jats:italic>i<\/jats:italic>\n                      <\/jats:sub>\n                      in brain and kidney resistance arterioles and capillaries that were blocked by pretreatment with the type 1 angiotensin II receptor inhibitor losartan, but not by the type 2 angiotensin II receptor inhibitor PD123319. VEC responded to acute angiotensin II by increased NO production as indicated by &gt;1.5\u2010fold increase in 4\u2010amino\u20105\u2010methylamino\u20102\u2032,7\u2032\u2010difluorofluorescein diacetate fluorescence intensity. In mice with kidney fibrosis or hypertension, the angiotensin II\u2013induced VEC [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>\n                        <jats:italic>i<\/jats:italic>\n                      <\/jats:sub>\n                      and NO responses were significantly reduced, which was associated with more robust vasoconstrictions, VEC shedding, and microthrombi formation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      The present study directly visualized angiotensin II\u2013induced increases in VEC [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>\n                        <jats:italic>i<\/jats:italic>\n                      <\/jats:sub>\n                      and NO production that serve to counterbalance agonist\u2010induced vasoconstriction and maintain residual organ blood flow. These direct and endothelium\u2010specific angiotensin II effects were blunted in disease conditions and linked to endothelial dysfunction and the development of vascular pathologies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.123.033998","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T06:34:38Z","timestamp":1715322878000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Angiotensin II Directly Increases Endothelial Calcium and Nitric Oxide in Kidney and Brain Microvessels In\u00a0Vivo With Reduced Efficacy in Hypertension"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8807-4099","authenticated-orcid":false,"given":"Alejandra","family":"Becerra Calderon","sequence":"first","affiliation":[{"name":"Department of Physiology and Neuroscience University of Southern California Los Angeles CA"},{"name":"Zilkha Neurogenetic Institute University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0651-2237","authenticated-orcid":false,"given":"Urvi Nikhil","family":"Shroff","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neuroscience University of Southern California Los Angeles CA"},{"name":"Zilkha Neurogenetic Institute University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin","family":"Deepak","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neuroscience University of Southern California Los Angeles CA"},{"name":"Zilkha Neurogenetic Institute University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0551-1287","authenticated-orcid":false,"given":"Audrey","family":"Izuhara","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neuroscience University of Southern California Los Angeles CA"},{"name":"Zilkha Neurogenetic Institute University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4780-4295","authenticated-orcid":false,"given":"Greta","family":"Trogen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neuroscience University of Southern California Los Angeles CA"},{"name":"Zilkha Neurogenetic Institute University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0459-469X","authenticated-orcid":false,"given":"Alicia A.","family":"McDonough","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neuroscience University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2659-6485","authenticated-orcid":false,"given":"Susan B.","family":"Gurley","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1456-9399","authenticated-orcid":false,"given":"Jonathan W.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4092-6185","authenticated-orcid":false,"given":"J\u00e1nos","family":"Peti\u2010Peterdi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neuroscience University of Southern California Los Angeles CA"},{"name":"Zilkha Neurogenetic Institute University of Southern California Los Angeles CA"},{"name":"Department of Medicine University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3452-7970","authenticated-orcid":false,"given":"Georgina","family":"Gyarmati","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neuroscience University of Southern California Los Angeles CA"},{"name":"Zilkha Neurogenetic Institute University of Southern California Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00038.2017"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.59.3.3"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.120.000236"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.602930"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.116.306531"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.107.149484"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801963105"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0006-2952(96)00691-0"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1159\/000342812"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.765356"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.152676"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.123392"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1556\/2060.2021.00205"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0306-3623(97)00021-9"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602715103"},{"key":"e_1_3_2_17_2","first-page":"678","article-title":"Intrarenal prostaglandin release attenuates the renal vasoconstrictor activity of angiotensin","volume":"184","author":"Aiken JW","year":"1973","unstructured":"Aiken JW, Vane JR. Intrarenal prostaglandin release attenuates the renal vasoconstrictor activity of angiotensin. J Pharmacol Exp Ther. 1973;184:678\u2013687.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1980.239.5.F486"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1998.274.1.C214"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-0834"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.26.5.752"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-009-0767-7"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20090449"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.18.2.165"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00287.2006"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09002"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.32417"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0925-4773(03)00099-6"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.112222199"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00106.2015"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00154.2021"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00029.2018"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3405"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00521.2005"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4489"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.111.253419"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14291"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.3791\/52734"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00489.2007"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.asn.0000088737.05283.2b"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200013020-00008"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215927110"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.3791\/58520"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00546.2020"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00037.2021"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.genm.2011.12.003"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1161\/hypertensionaha.111.173013"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1097\/ccm.0000000000003569"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2021.111255"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq004"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.02.009"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.110.222844"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.115.305995"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1177\/14703203010020010801"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1139\/cjpp-2017-0280"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1139\/cjpp-2017-0416"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2008.158"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1042\/cs20171598"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-007-0026-2"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605545103"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2009.86"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1042\/cs20060342"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4641"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00016.2011"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400581"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00417.2015"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.123.033998","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T02:17:23Z","timestamp":1717726643000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.123.033998"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,21]]},"references-count":65,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,5,21]]}},"alternative-id":["10.1161\/JAHA.123.033998"],"URL":"https:\/\/doi.org\/10.1161\/jaha.123.033998","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,21]]},"assertion":[{"value":"2024-02-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e033998"}}