{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:11:07Z","timestamp":1787508667898,"version":"build-2736575974"},"reference-count":29,"publisher":"American Physiological Society","issue":"5","funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL088554"],"award-info":[{"award-number":["HL088554"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL142808"],"award-info":[{"award-number":["HL142808"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL007284"],"award-info":[{"award-number":["HL007284"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000963","name":"The American Diabetes Association Research Foundation","doi-asserted-by":"publisher","award":["1-19-JDF-111"],"award-info":[{"award-number":["1-19-JDF-111"]}],"id":[{"id":"10.13039\/100000963","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2020,5,1]]},"abstract":"<jats:p>Discrete calcium signals within the vascular endothelium decrease with age and contribute to impaired endothelial-dependent vasodilation. Calreticulin (Calr), a multifunctional calcium binding protein and endoplasmic reticulum (ER) chaperone, can mediate calcium signals and vascular function within the endothelial cells (ECs) of small resistance arteries. We found Calr protein expression significantly decreases with age in mesenteric arteries and examined the functional role of EC Calr in vasodilation and calcium mobilization in the context of aging. Third-order mesenteric arteries from mice with or without EC Calr knockdown were examined for calcium signals and constriction to phenylephrine (PE) or vasodilation to carbachol (CCh) after 75 wk of age. PE constriction in aged mice with or without EC Calr was unchanged. However, calcium signals and vasodilation to endothelial-dependent agonist carbachol were significantly impaired in aged EC Calr knockdown mice. Ex vivo incubation of arteries with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) significantly improved vasodilation in mice lacking EC Calr. Our data suggests diminished vascular Calr expression with age can contribute to the detrimental effects of aging on endothelial calcium regulation and vasodilation.<\/jats:p>\n                  <jats:p>NEW &amp; NOTEWORTHY Calreticulin (Calr) is responsible for key physiological processes in endoplasmic reticulum, especially in aging tissue. In particular, endothelial Calr is crucial to vascular function. In this study, we deleted Calr from the endothelium and aged the mice up to 75 wk to examine changes in vascular function. We found two key differences: 1) calcium events in endothelium were severely diminished after muscarinic stimulation, which 2) corresponded with a dramatic decrease in muscarinic vasodilation. Remarkably, we were able to rescue the effect of Calr deletion on endothelial-dependent vasodilatory function using tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum stress that is currently in clinical trials.<\/jats:p>","DOI":"10.1152\/ajpheart.00586.2019","type":"journal-article","created":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T12:01:37Z","timestamp":1584705697000},"page":"H1041-H1048","source":"Crossref","is-referenced-by-count":18,"title":["Endothelial calreticulin deletion impairs endothelial function in aged mice"],"prefix":"10.1152","volume":"318","author":[{"given":"Lauren A.","family":"Biwer","sequence":"first","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia"},{"name":"Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia"},{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8521-6828","authenticated-orcid":false,"given":"Henry R.","family":"Askew-Page","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia"},{"name":"Vascular Biology Research Centre, Institute of Molecular and Clinical Sciences, St. George\u2019s University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangseok","family":"Hong","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia"},{"name":"Department of Physical Education, College of Education, Chung-Ang University, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Milstein","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1920-5033","authenticated-orcid":false,"given":"Scott R.","family":"Johnstone","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Macal","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda E.","family":"Good","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia"},{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooneh","family":"Bagher","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M University Health Science Center, Bryan, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swapnil K.","family":"Sonkusare","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia"},{"name":"Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brant E.","family":"Isakson","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia"},{"name":"Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R900011-JLR200"},{"key":"B2","doi-asserted-by":"crossref","first-page":"21458","DOI":"10.1016\/S0021-9258(18)54661-5","volume":"266","author":"Baksh S","year":"1991","journal-title":"J Biol Chem"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5431-11.2012"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309886"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00038.2016"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/61.5.435"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.042699099"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aal3806"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.27.4.849"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-145482"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.310038"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2018.08.008"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202405200"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.984047"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508302200"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1042\/bj3440281"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20081847"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2009.03.001"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200102073"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1113\/JP278255"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.1448"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2003.09.017"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1549-8719.2011.00146.x"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/science.1216283"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2005052"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1316-16.2016"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00042.2013"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2014.00447"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.7453\/gahmj.2014.017"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00586.2019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T04:02:56Z","timestamp":1614916976000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpheart.00586.2019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,1]]},"references-count":29,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,5,1]]}},"alternative-id":["10.1152\/ajpheart.00586.2019"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00586.2019","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,1]]}}}