{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T01:23:31Z","timestamp":1778030611434,"version":"3.51.4"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2020,12,15]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Abnormal endothelial function in the lungs is implicated in the development of pulmonary hypertension; however, there is little information about the difference of endothelial function between small distal pulmonary artery (PA) and large proximal PA and their contribution to the development of pulmonary hypertension. Herein, we investigate endothelium\u2010dependent relaxation in different orders of PAs and examine the molecular mechanisms by which chronic hypoxia attenuates endothelium\u2010dependent pulmonary vasodilation, leading to pulmonary hypertension.<\/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              Endothelium\u2010dependent relaxation in large proximal PAs (second order) was primarily caused by releasing NO from the endothelium, whereas endothelium\u2010dependent hyperpolarization (EDH)\u2013mediated vasodilation was prominent in small distal PAs (fourth\u2013fifth order). Chronic hypoxia abolished EDH\u2010mediated relaxation in small distal PAs without affecting smooth muscle\u2013dependent relaxation. RNA\u2010sequencing data revealed that, among genes related to EDH, the levels of\n              <jats:italic>Cx37<\/jats:italic>\n              ,\n              <jats:italic>Cx40<\/jats:italic>\n              ,\n              <jats:italic>Cx43<\/jats:italic>\n              , and\n              <jats:italic>IK<\/jats:italic>\n              were altered in mouse pulmonary endothelial cells isolated from chronically hypoxic mice in comparison to mouse pulmonary endothelial cells from normoxic control mice. The protein levels were significantly lower for connexin 40 (Cx40) and higher for connexin 37 in mouse pulmonary endothelial cells from hypoxic mice than normoxic mice. Cx40 knockout mice exhibited significant attenuation of EDH\u2010mediated relaxation and marked increase in right ventricular systolic pressure. Interestingly, chronic hypoxia led to a further increase in right ventricular systolic pressure in Cx40 knockout mice without altering EDH\u2010mediated relaxation. Furthermore, overexpression of Cx40 significantly decreased right ventricular systolic pressure in chronically hypoxic mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">These data suggest that chronic hypoxia\u2010induced downregulation of endothelial Cx40 results in impaired EDH\u2010mediated relaxation in small distal PAs and contributes to the development of pulmonary hypertension.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.120.018327","type":"journal-article","created":{"date-parts":[[2020,12,12]],"date-time":"2020-12-12T10:01:49Z","timestamp":1607767309000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Chronic Hypoxia Decreases Endothelial Connexin 40, Attenuates Endothelium\u2010Dependent Hyperpolarization\u2013Mediated Relaxation in Small Distal Pulmonary Arteries, and Leads to Pulmonary Hypertension"],"prefix":"10.1161","volume":"9","author":[{"given":"Rui","family":"Si","sequence":"first","affiliation":[{"name":"Department of Physiology The University of Arizona Tucson AZ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology The University of Arizona Tucson AZ"},{"name":"State Key Laboratory of Respiratory Disease The First Affiliated Hospital of Guangzhou Medical University Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jody Tori O.","family":"Cabrera","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiuyu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego CA"},{"name":"State Key Laboratory of Respiratory Disease The First Affiliated Hospital of Guangzhou Medical University Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8226-2618","authenticated-orcid":false,"given":"Atsumi","family":"Tsuji\u2010Hosokawa","sequence":"additional","affiliation":[{"name":"Department of Physiology The University of Arizona Tucson AZ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makiko","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Physiology The University of Arizona Tucson AZ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susumu","family":"Hosokawa","sequence":"additional","affiliation":[{"name":"Department of Medicine The University of Arizona Tucson AZ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingmei","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego CA"},{"name":"State Key Laboratory of Respiratory Disease The First Affiliated Hospital of Guangzhou Medical University Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pritesh P.","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony W.","family":"Ashton","sequence":"additional","affiliation":[{"name":"Division of Perinatal Research Kolling Institute of Medical ResearchUniversity of Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason X.\u2010J.","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Medicine The University of Arizona Tucson AZ"},{"name":"Department of Medicine University of California San Diego CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine The University of Arizona Tucson AZ"},{"name":"Department of Medicine University of California San Diego CA"},{"name":"State Key Laboratory of Respiratory Disease The First Affiliated Hospital of Guangzhou Medical University Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1259-8604","authenticated-orcid":false,"given":"Ayako","family":"Makino","sequence":"additional","affiliation":[{"name":"Department of Physiology The University of Arizona Tucson AZ"},{"name":"Department of Medicine The University of Arizona Tucson AZ"},{"name":"Department of Medicine University of California San Diego CA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/739674"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11325-015-1175-1"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2012.069112"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1992.tb12759.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00313.2012"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1569-9048(02)00053-8"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00487.2017"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-63245-2_6"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2010.05557.x"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12649"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/micc.12255"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2008.2117"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2003.11.013"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1681.2002.03699.x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.3.341"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00042.2013"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2005.11.002"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00007.2003"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.6.649"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2011.11.012"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7370"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002423"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00169.2002"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7892609"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.171305298"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-008-0309-4"},{"key":"e_1_3_2_28_2","first-page":"4674","article-title":"Sildenefil increases connexin 40 in smooth muscle cells through activation of BMP pathways in pulmonary arterial hypertension","volume":"7","author":"Yang L","year":"2014","unstructured":"Yang L, Yin N, Hu L, Fan H, Yu D, Zhang W, Wang S, Feng Y, Fan C, Cao F, et al. Sildenefil increases connexin 40 in smooth muscle cells through activation of BMP pathways in pulmonary arterial hypertension. Int J Clin Exp Pathol. 2014;7:4674\u20134684.","journal-title":"Int J Clin Exp Pathol"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19071891"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.013339"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00719.2012"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.04578"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00433.2007"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12646"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1086\/690206"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14864"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1993.tb13611.x"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.244798"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205934200"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082594"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0097687"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2012.066340"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-12-30"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00169-2019"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1177\/2045894020937134"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.05.097"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.202572"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01742-7"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.120.018327","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T11:03:53Z","timestamp":1715598233000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.120.018327"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,15]]},"references-count":47,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2020,12,15]]}},"alternative-id":["10.1161\/JAHA.120.018327"],"URL":"https:\/\/doi.org\/10.1161\/jaha.120.018327","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,15]]},"assertion":[{"value":"2020-08-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e018327"}}