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The pulmonary artery endothelial cell (PAEC) inflammation, and pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy and collagen remodelling are the important pathophysiological components of PVR. Endogenous sulfur dioxide (SO<jats:sub>2<\/jats:sub>) was found to be a novel gasotransmitter in the cardiovascular system with its unique biological properties. The study was aimed to investigate the role of endothelial cell\u2010 (EC\u2010) derived SO<jats:sub>2<\/jats:sub> in the progression of PAEC inflammation, PASMC proliferation, hypertrophy and collagen remodelling in PVR and the possible mechanisms. EC\u2010specific aspartic aminotransferase 1 transgenic (EC\u2010AAT1\u2010Tg) mice were constructed <jats:italic>in vivo<\/jats:italic>. Pulmonary hypertension was induced by hypoxia. Right heart catheterization and echocardiography were used to detect mouse hemodynamic changes. Pathologic analysis was performed in the pulmonary arteries. High\u2010performance liquid chromatography was employed to detect the SO<jats:sub>2<\/jats:sub> content. Human PAECs (HPAECs) with lentiviruses containing AAT1 cDNA or shRNA and cocultured human PASMCs (HPASMCs) were applied <jats:italic>in vitro<\/jats:italic>. SO<jats:sub>2<\/jats:sub> probe and enzyme\u2010linked immunosorbent assay were used to detect the SO<jats:sub>2<\/jats:sub> content and determine p50 activity, respectively. Hypoxia caused a significant reduction in SO<jats:sub>2<\/jats:sub> content in the mouse lung and HPAECs and increases in right ventricular systolic pressure, pulmonary artery wall thickness, muscularization, and the expression of PAEC ICAM\u20101 and MCP\u20101 and of PASMC Ki\u201067, collagen I, and <jats:italic>\u03b1<\/jats:italic>\u2010SMA (<jats:italic>p<\/jats:italic> &lt; 0.05). However, EC\u2010AAT1\u2010Tg with sufficient SO<jats:sub>2<\/jats:sub> content prevented the above increases induced by hypoxia (<jats:italic>p<\/jats:italic> &lt; 0.05). Mechanistically, EC\u2010derived SO<jats:sub>2<\/jats:sub> deficiency promoted HPAEC ICAM\u20101 and MCP\u20101 and the cocultured HPASMC Ki\u201067 and collagen I expression, which was abolished by andrographolide, an inhibitor of p50 (<jats:italic>p<\/jats:italic> &lt; 0.05). Meanwhile, EC\u2010derived SO<jats:sub>2<\/jats:sub> deficiency increased the expression of cocultured HPASMC <jats:italic>\u03b1<\/jats:italic>\u2010SMA (<jats:italic>p<\/jats:italic> &lt; 0.05). Taken together, these findings revealed that EC\u2010derived SO<jats:sub>2<\/jats:sub> inhibited p50 activation to control PAEC inflammation in an autocrine manner and PASMC proliferation, hypertrophy, and collagen synthesis in a paracrine manner, thereby inhibiting hypoxic PVR.<\/jats:p>","DOI":"10.1155\/2021\/5577634","type":"journal-article","created":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T01:20:09Z","timestamp":1618708809000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Endothelial Cell\u2010Derived SO<sub>2<\/sub> Controls Endothelial Cell Inflammation, Smooth Muscle Cell Proliferation, and Collagen Synthesis to Inhibit Hypoxic Pulmonary Vascular Remodelling"],"prefix":"10.1155","volume":"2021","author":[{"given":"Xin","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chufan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guozhen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guosheng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghong","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingfang","family":"Bu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8346-3809","authenticated-orcid":false,"given":"Yaqian","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9036-4980","authenticated-orcid":false,"given":"Junbao","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1606-8988","authenticated-orcid":false,"given":"Hongfang","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,4,17]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.10865"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.246876"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0b013e328353e501"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(18)30103-6"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2017.06.006"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2008.06.001"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1183\/09059180.00007913"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j5492"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.11-0793"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2019.101099"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201001-0011OC"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306806"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1042\/CS20190514"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2016.129"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/2502843"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/5641645"},{"key":"e_1_2_9_17_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201696150"},{"key":"e_1_2_9_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.01568"},{"key":"e_1_2_9_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309212"},{"key":"e_1_2_9_20_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm5040045"},{"key":"e_1_2_9_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7254.2008.00845.x"},{"key":"e_1_2_9_22_2","first-page":"999","article-title":"Effect 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