{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:38:06Z","timestamp":1790707086030,"version":"4.1.0"},"reference-count":130,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T00:00:00Z","timestamp":1662076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pulmonary arterial hypertension is a multifactorial, chronic disease process that leads to pulmonary arterial endothelial dysfunction and smooth muscular hypertrophy, resulting in impaired pliability and hemodynamics of the pulmonary vascular system, and consequent right ventricular dysfunction. Existing treatments target limited pathways with only modest improvement in disease morbidity, and little or no improvement in mortality. Ongoing research has focused on the molecular basis of pulmonary arterial hypertension and is going to be important in the discovery of new treatments and genetic pathways involved. This review focuses on the molecular pathogenesis of pulmonary arterial hypertension.<\/jats:p>","DOI":"10.3390\/ijms231710001","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T05:17:23Z","timestamp":1662441443000},"page":"10001","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Molecular Pathways in Pulmonary Arterial Hypertension"],"prefix":"10.3390","volume":"23","author":[{"given":"Aangi J.","family":"Shah","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mounica","family":"Vorla","sequence":"additional","affiliation":[{"name":"Division of Cardiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5254-4067","authenticated-orcid":false,"given":"Dinesh K.","family":"Kalra","sequence":"additional","affiliation":[{"name":"Division of Cardiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1053\/j.jvca.2021.06.036","article-title":"Pulmonary Hypertension in 2021: Part I\u2014Definition, Classification, Pathophysiology, and Presentation","volume":"36","author":"Gelzinis","year":"2022","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1161\/CIRCULATIONAHA.115.020207","article-title":"Association of Borderline Pulmonary Hypertension with Mortality and Hospitalization in a Large Patient Cohort: Insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program","volume":"133","author":"Maron","year":"2016","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/ejhf.1570","article-title":"Mildly increased pulmonary arterial pressure: A new disease entity or just a marker of poor prognosis?","volume":"21","author":"Kovacs","year":"2019","journal-title":"Eur. J. Heart Fail."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1002\/art.37838","article-title":"Borderline Mean Pulmonary Artery Pressure in Patients with Systemic Sclerosis: Transpulmonary Gradient Predicts Risk of Developing Pulmonary Hypertension","volume":"65","author":"Valerio","year":"2012","journal-title":"Arthritis Care Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1136\/annrheumdis-2011-200546","article-title":"Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: Results from the PHAROS registry","volume":"71","author":"Bae","year":"2012","journal-title":"Ann. Rheum. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"888","DOI":"10.12688\/f1000research.18811.1","article-title":"The 6th World Symposium on Pulmonary Hypertension: What\u2019s old is new","volume":"8","author":"Condon","year":"2019","journal-title":"F1000Research"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/S2213-2600(15)00543-3","article-title":"A global view of pulmonary hypertension","volume":"4","author":"Hoeper","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"D51","DOI":"10.1016\/j.jacc.2013.10.023","article-title":"Pulmonary Arterial Hypertension: Epidemiology and registries","volume":"62","author":"McGoon","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"j5492","DOI":"10.1136\/bmj.j5492","article-title":"Pulmonary arterial hypertension: Pathogenesis and clinical management","volume":"360","author":"Thenappan","year":"2018","journal-title":"BMJ"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1378\/chest.13-3061","article-title":"Sex Differences in Response to Pulmonary Arterial Hypertension Therapy: Is what\u2019s good for the goose, good for the gander?","volume":"145","author":"Hatton","year":"2014","journal-title":"Chest"},{"key":"ref_11","unstructured":"Maron, B.A. (2021). Pulmonary Hypertension. Braunwald\u2019s Heart Disease, Single Volume: A Textbook of Cardiovascular Medicine, Elsevier. [12th ed.]."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"210053","DOI":"10.1183\/16000617.0053-2021","article-title":"Pulmonary hypertension phenotypes in patients with systemic sclerosis","volume":"30","author":"Haque","year":"2021","journal-title":"Eur. Respir. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0140-6736(14)60844-8","article-title":"Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990\u20132013: A systematic analysis for the Global Burden of Disease Study 2013","volume":"384","author":"Murray","year":"2014","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"608883","DOI":"10.3389\/fimmu.2020.608883","article-title":"Schistosomiasis Pulmonary Arterial Hypertension","volume":"11","author":"Sibomana","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110483","DOI":"10.1016\/j.mehy.2021.110483","article-title":"COVID-19 patients may become predisposed to pulmonary arterial hypertension","volume":"147","author":"Suzuki","year":"2021","journal-title":"Med. Hypotheses"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1161\/CIRCULATIONAHA.110.015008","article-title":"Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Results from an international prospective registry","volume":"124","author":"Delcroix","year":"2011","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1056\/NEJMp048088","article-title":"Chronic Thromboembolic Pulmonary Hypertension\u2014Not So Rare after All","volume":"350","author":"Lang","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.hfc.2018.02.009","article-title":"Chronic Thromboembolic Pulmonary Hypertension","volume":"14","author":"Mullin","year":"2018","journal-title":"Heart Fail. Clin."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Valerio, L., Mavromanoli, A.C., Barco, S., Abele, C., Becker, D., Bruch, L., Ewert, R., Faehling, M., Fistera, D., and Gerhardt, F. (2022). Chronic thromboembolic pulmonary hypertension and impairment after pulmonary embolism: The FOCUS study. Eur. Heart J., ehac206.","DOI":"10.1093\/eurheartj\/ehac544.1901"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"160121","DOI":"10.1183\/16000617.0121-2016","article-title":"An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan","volume":"26","author":"Gall","year":"2017","journal-title":"Eur. Respir. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1177\/1076029611431956","article-title":"Long-Term Outcomes in Acute Pulmonary Thromboembolism: The incidence of chronic thromboembolic pulmonary hypertension and associated risk factors","volume":"18","author":"Korkmaz","year":"2012","journal-title":"Clin. Appl. Thromb."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.thromres.2010.12.010","article-title":"Echocardiographic assessment of pulmonary arterial pressure in the follow-up of patients with pulmonary embolism","volume":"127","author":"Otero","year":"2011","journal-title":"Thromb. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1007\/s11239-010-0452-x","article-title":"Incidence of recurrent venous thromboembolism and of chronic thromboembolic pulmonary hypertension in patients after a first episode of pulmonary embolism","volume":"30","author":"Poli","year":"2010","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1056\/NEJMoa032274","article-title":"Incidence of Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Embolism","volume":"350","author":"Pengo","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1097\/01.md.0000236952.87590.c8","article-title":"Survival and Restoration of Pulmonary Perfusion in a Long-Term Follow-Up of Patients After Acute Pulmonary Embolism","volume":"85","author":"Miniati","year":"2006","journal-title":"Medicine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1378\/chest.130.1.172","article-title":"Incidence of Chronic Thromboembolic Pulmonary Hypertension After a First Episode of Pulmonary Embolism","volume":"130","author":"Becattini","year":"2006","journal-title":"Chest"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.thromres.2009.01.003","article-title":"Incidence of chronic pulmonary hypertension in patients with previous pulmonary embolism","volume":"124","author":"Dentali","year":"2009","journal-title":"Thromb. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"970","DOI":"10.3324\/haematol.2009.018960","article-title":"Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism","volume":"95","author":"Klok","year":"2010","journal-title":"Haematologica"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.chest.2020.02.035","article-title":"Pulmonary Hypertension by the Method of Paul Wood","volume":"158","author":"Newman","year":"2020","journal-title":"Chest"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1801913","DOI":"10.1183\/13993003.01913-2018","article-title":"Haemodynamic definitions and updated clinical classification of pulmonary hypertension","volume":"53","author":"Simonneau","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1801897","DOI":"10.1183\/13993003.01897-2018","article-title":"Pulmonary hypertension due to left heart disease","volume":"53","author":"Tedford","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1515\/hkbrd-2016-0004","article-title":"Review of the diagnosis and pharmacological management of pulmonary arterial hypertension in connective tissue disease","volume":"16","author":"Tang","year":"2016","journal-title":"Hong Kong Bull. Rheum. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rizzo, A.N., Fraidenburg, D.R., and Yuan, J.X.J. (2015). Pulmonary Vascular Anatomy. PanVascular Medicine, Springer.","DOI":"10.1007\/978-3-642-37078-6_201"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1002\/cphy.c100081","article-title":"Structure and Composition of Pulmonary Arteries, Capillaries, and Veins","volume":"2","author":"Townsley","year":"2012","journal-title":"Compr. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.cca.2009.01.018","article-title":"Molecular mechanisms of pulmonary hypertension","volume":"403","author":"Yildiz","year":"2009","journal-title":"Clin. Chim. Acta"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2003957","DOI":"10.1183\/13993003.03957-2020","article-title":"Endothelial cells in the pathogenesis of pulmonary arterial hypertension","volume":"58","author":"Evans","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-3-642-38664-0_2","article-title":"Pulmonary hypertension: Pathophysiology and signaling Pathways","volume":"218","author":"Maron","year":"2013","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1161\/CIRCULATIONAHA.108.847707","article-title":"Basic Science of Pulmonary Arterial Hypertension for Clinicians","volume":"121","author":"Archer","year":"2010","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1801887","DOI":"10.1183\/13993003.01887-2018","article-title":"Pathology and pathobiology of pulmonary hypertension: State of the art and research perspectives","volume":"53","author":"Humbert","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1161\/CIRCULATIONAHA.106.632208","article-title":"Right Ventricular Function and Failure","volume":"114","author":"Voelkel","year":"2006","journal-title":"Circulation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jacc.2016.10.047","article-title":"The Relationship Between the Right Ventricle and its Load in Pulmonary Hypertension","volume":"69","author":"Westerhof","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1056\/NEJM200108023450502","article-title":"Mutation in the Gene for Bone Morphogenetic Protein Receptor II as a Cause of Primary Pulmonary Hypertension in a Large Kindred","volume":"345","author":"Newman","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1164\/rccm.202004-1411ED","article-title":"Clarifying the Pulmonary Arterial Hypertension Molecular Landscape Using Functional Genetics","volume":"202","author":"Maron","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_44","first-page":"59","article-title":"Is nitric oxide a hormone?","volume":"15","author":"Ghasemi","year":"2011","journal-title":"Iran Biomed. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1038\/jp.2008.161","article-title":"Role of iNO in the modulation of pulmonary vascular resistance","volume":"28","author":"Schreiber","year":"2008","journal-title":"J. Perinatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1161\/ATVBAHA.107.142943","article-title":"Nitric Oxide in the Pulmonary Vasculature","volume":"27","author":"Coggins","year":"2007","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"20","DOI":"10.4103\/2045-8932.109911","article-title":"Nitric Oxide Deficiency in Pulmonary Hypertension: Pathobiology and Implications for Therapy","volume":"3","author":"Tonelli","year":"2013","journal-title":"Pulm. Circ."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"L15","DOI":"10.1152\/ajplung.00322.2006","article-title":"The lung in the balance: Arginine, methylated arginines, and nitric oxide","volume":"292","author":"Dweik","year":"2007","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1161\/01.CIR.0000162470.26840.89","article-title":"Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension","volume":"111","author":"Khoo","year":"2005","journal-title":"Circulation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1056\/NEJM199507273330403","article-title":"Reduced Expression of Endothelial Nitric Oxide Synthase in the Lungs of Patients with Pulmonary Hypertension","volume":"333","author":"Giaid","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1056\/NEJM199512143332416","article-title":"Endothelial Nitric Oxide Synthase in the Lungs of Patients with Pulmonary Hypertension","volume":"333","author":"Xue","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/(SICI)1096-9896(199807)185:3<313::AID-PATH93>3.0.CO;2-8","article-title":"High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension","volume":"185","author":"Mason","year":"1998","journal-title":"J. Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"33134","DOI":"10.1074\/jbc.M111.274100","article-title":"Bone Morphogenetic Protein Receptor II Is a Novel Mediator of Endothelial Nitric-oxide Synthase Activation","volume":"286","author":"Gangopahyay","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jare.2018.03.005","article-title":"Synopsis of arachidonic acid metabolism: A review","volume":"11","author":"Hanna","year":"2018","journal-title":"J. Adv. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1056\/NEJM199207093270202","article-title":"An Imbalance between the Excretion of Thromboxane and Prostacyclin Metabolites in Pulmonary Hypertension","volume":"327","author":"Christman","year":"1992","journal-title":"N. Engl. J. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"L654","DOI":"10.1152\/ajplung.00229.2006","article-title":"Thromboxane hypersensitivity in hypoxic pulmonary artery myocytes: Altered TP receptor localization and kinetics","volume":"292","author":"Hinton","year":"2007","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1164\/ajrccm.159.6.9804054","article-title":"Prostacyclin Synthase Expression Is Decreased in Lungs from Patients with Severe Pulmonary Hypertension","volume":"159","author":"Tuder","year":"1999","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.1056\/NEJMoa1503184","article-title":"Selexipag for the Treatment of Pulmonary Arterial Hypertension","volume":"373","author":"Sitbon","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1183\/09059180.00008411","article-title":"Pulmonary hypertension: The science behind the disease spectrum","volume":"21","author":"Wilkins","year":"2012","journal-title":"Eur. Respir. Rev."},{"key":"ref_60","first-page":"62","article-title":"The role of endothelin-1 in pulmonary arterial hypertension","volume":"2014","author":"Chester","year":"2014","journal-title":"Glob. Cardiol. Sci. Pract."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"405","DOI":"10.21037\/cdt.2017.04.11","article-title":"Pulmonary hypertension: Diagnosis, imaging techniques, and novel therapies","volume":"7","author":"Goldberg","year":"2017","journal-title":"Cardiovasc. Diagn. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.yjmcc.2007.09.006","article-title":"Pathogenic mechanisms of pulmonary arterial hypertension","volume":"44","author":"Chan","year":"2008","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.mvr.2004.06.001","article-title":"Cellular and molecular mechanisms of pulmonary vascular remodeling: Role in the development of pulmonary hypertension","volume":"68","author":"Mandegar","year":"2004","journal-title":"Microvasc. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1161\/CIRCULATIONAHA.105.591321","article-title":"Cross Talk Between Endothelial and Smooth Muscle Cells in Pulmonary Hypertension","volume":"113","author":"Eddahibi","year":"2006","journal-title":"Circulation"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1056\/NEJMra035488","article-title":"Pulmonary arterial hypertension","volume":"351","author":"Farber","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1161\/01.CIR.0000091409.53101.E8","article-title":"Polymorphism of the Serotonin Transporter Gene and Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease","volume":"108","author":"Eddahibi","year":"2003","journal-title":"Circulation"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4306","DOI":"10.1172\/JCI60658","article-title":"Molecular pathogenesis of pulmonary arterial hypertension","volume":"122","author":"Rabinovitch","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1161\/01.CIR.0000127375.56172.92","article-title":"Overexpression of the 5-Hydroxytryptamine Transporter Gene","volume":"109","author":"MacLean","year":"2004","journal-title":"Circulation"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1161\/01.RES.0000222546.45372.a0","article-title":"Transgenic Mice Overexpressing the 5-Hydroxytryptamine Transporter Gene in Smooth Muscle Develop Pulmonary Hypertension","volume":"98","author":"Guignabert","year":"2006","journal-title":"Circ. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1172\/JCI8678","article-title":"Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene","volume":"105","author":"Eddahibi","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1056\/NEJM199608293350901","article-title":"Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension","volume":"335","author":"Abenhaim","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1164\/rccm.200210-1212OC","article-title":"Serotonin Transporter Inhibitors Protect against Hypoxic Pulmonary Hypertension","volume":"168","author":"Marcos","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s11658-020-00237-6","article-title":"Upregulation of miR-361-3p suppresses serotonin-induced proliferation in human pulmonary artery smooth muscle cells by targeting SERT","volume":"25","author":"Zhang","year":"2020","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_74","first-page":"w14202","article-title":"Swiss Society of Pulmonary Hypertension. The pathogenesis of pulmonary hypertension\u2014An update","volume":"145","author":"Huber","year":"2015","journal-title":"Swiss Med. Wkly."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1177\/1753465809369619","article-title":"PPAR\u03a5 as a potential therapeutic target in pulmonary hypertension","volume":"4","author":"Sutliff","year":"2010","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_76","first-page":"381","article-title":"Treatment of PAH with a PPAR\u03b3 agonist","volume":"15","author":"Lim","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"eaap7294","DOI":"10.1126\/scitranslmed.aap7294","article-title":"NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension","volume":"10","author":"Samokhin","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2002341","DOI":"10.1183\/13993003.02341-2020","article-title":"Targeting transforming growth factor-\u03b2 receptors in pulmonary hypertension","volume":"57","author":"Guignabert","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1007\/s00018-017-2510-4","article-title":"BMP type II receptor as a therapeutic target in pulmonary arterial hypertension","volume":"74","author":"Orriols","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_80","first-page":"e202003","article-title":"Pulmonary arterial hypertension: Cellular and molecular changes in the lung","volume":"2020","author":"Maron","year":"2020","journal-title":"Glob. Cardiol. Sci. Pract."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Leopold, J.A., and Maron, B.A. (2016). Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050761"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.1002\/jcp.26195","article-title":"Bone morphogenetic protein-7 inhibits endothelial-mesenchymal transition in pulmonary artery endothelial cell under hypoxia","volume":"233","author":"Zhang","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1161\/CIRCULATIONAHA.115.020617","article-title":"In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug","volume":"133","author":"Hopper","year":"2016","journal-title":"Circulation"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1161\/CIRCULATIONAHA.114.008750","article-title":"Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension","volume":"131","author":"Ranchoux","year":"2015","journal-title":"Circulation"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"11418","DOI":"10.1073\/pnas.0610467104","article-title":"The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted","volume":"104","author":"Bonnet","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1164\/rccm.201604-0814OC","article-title":"MicroRNA-138 and MicroRNA-25 Down-regulate Mitochondrial Calcium Uniporter, Causing the Pulmonary Arterial Hypertension Cancer Phenotype","volume":"195","author":"Hong","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1253\/circj.CJ-09-0135","article-title":"Evidence for Rho-Kinase Activation in Patients with Pulmonary Arterial Hypertension","volume":"73","author":"Do","year":"2009","journal-title":"Circ. J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1164\/rccm.200805-691OC","article-title":"RhoA and Rho Kinase Activation in Human Pulmonary Hypertension","volume":"179","author":"Guilluy","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pupt.2010.09.001","article-title":"Key role of the RhoA\/Rho kinase system in pulmonary hypertension","volume":"24","author":"Connolly","year":"2011","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1161\/CIRCULATIONAHA.117.028069","article-title":"Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124\/PTBP1 (Polypyrimidine Tract Binding Protein 1)\/Pyruvate Kinase Muscle Axis","volume":"136","author":"Zhang","year":"2017","journal-title":"Circulation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1542\/peds.2005-1226","article-title":"Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children","volume":"117","author":"Stacpoole","year":"2006","journal-title":"Pediatrics"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1161\/01.RES.0000145360.16770.9f","article-title":"Dichloroacetate Prevents and Reverses Pulmonary Hypertension by Inducing Pulmonary Artery Smooth Muscle Cell Apoptosis","volume":"95","author":"McMurtry","year":"2004","journal-title":"Circ. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1056\/NEJMra1215233","article-title":"Mitochondrial Dynamics\u2014Mitochondrial Fission and Fusion in Human Diseases","volume":"369","author":"Archer","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_94","first-page":"1484","article-title":"Dynamin-Related Protein 1\u2013Mediated Mitochondrial Mitotic Fission Permits Hyperproliferation of Vascular Smooth Muscle Cells and Offers a Novel Therapeutic Target in Pulmonary Hypertension","volume":"110","author":"Marsboom","year":"2012","journal-title":"Clin. Trans. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.ccm.2020.10.005","article-title":"Sex Differences in Pulmonary Hypertension","volume":"42","author":"Morris","year":"2021","journal-title":"Clin. Chest Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1164\/rccm.201410-1802OC","article-title":"Sex Affects Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Artery Smooth Muscle Cells","volume":"191","author":"Mair","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/978-3-319-77932-4_31","article-title":"The Role of Sex in the Pathophysiology of Pulmonary Hypertension","volume":"1065","author":"Docherty","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1164\/rccm.201403-0483OC","article-title":"Sex-Dependent Influence of Endogenous Estrogen in Pulmonary Hypertension","volume":"190","author":"Mair","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1164\/rccm.201605-1024OC","article-title":"Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial","volume":"195","author":"Kawut","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1183\/09031936.00000508","article-title":"Insulin resistance in pulmonary arterial hypertension","volume":"33","author":"Zamanian","year":"2008","journal-title":"Eur. Respir. J."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1172\/JCI118228","article-title":"Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension","volume":"96","author":"Morrell","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1086\/675984","article-title":"The Role of the Renin-Angiotensin-Aldosterone System in the Pathobiology of Pulmonary Arterial Hypertension (2013 Grover Conference Series)","volume":"4","author":"Maron","year":"2014","journal-title":"Pulm. Circ."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S0008-6363(97)00049-7","article-title":"Right ventricular angiotensin converting enzyme activity and expression is increased during hypoxic pulmonary hypertension","volume":"34","author":"Morrell","year":"1997","journal-title":"Cardiovasc. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"H1186","DOI":"10.1152\/ajpheart.1995.269.4.H1186","article-title":"Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension","volume":"269","author":"Morrell","year":"1995","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1164\/rccm.201203-0411OC","article-title":"Dysregulated Renin\u2013Angiotensin\u2013Aldosterone System Contributes to Pulmonary Arterial Hypertension","volume":"186","author":"Tu","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1161\/CIRCULATIONAHA.112.094722","article-title":"Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and Modulate Pulmonary Arterial Hypertension","volume":"126","author":"Maron","year":"2012","journal-title":"Circulation"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/humu.9398","article-title":"BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension","volume":"27","author":"Aldred","year":"2006","journal-title":"Hum. Mutat."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1086\/303059","article-title":"Familial Primary Pulmonary Hypertension (Gene PPH1) Is Caused by Mutations in the Bone Morphogenetic Protein Receptor\u2013II Gene","volume":"67","author":"Deng","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/79226","article-title":"Heterozygous germline mutations in BMPR2, encoding a TGF-\u03b2 receptor, cause familial primary pulmonary hypertension","volume":"26","author":"Lane","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1056\/NEJMra2000348","article-title":"Pulmonary Arterial Hypertension","volume":"385","author":"Hassoun","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1165\/rcmb.2013-0100OC","article-title":"Correction of Nonsense BMPR2 and SMAD9 Mutations by Ataluren in Pulmonary Arterial Hypertension","volume":"49","author":"Drake","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3180","DOI":"10.1093\/hmg\/ddn214","article-title":"Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: Potential for rescue","volume":"17","author":"Sobolewski","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3600","DOI":"10.1172\/JCI65592","article-title":"FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension","volume":"123","author":"Spiekerkoetter","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1161\/CIRCRESAHA.111.300483","article-title":"Chloroquine Prevents Progression of Experimental Pulmonary Hypertension via Inhibition of Autophagy and Lysosomal Bone Morphogenetic Protein Type II Receptor Degradation","volume":"112","author":"Long","year":"2013","journal-title":"Circ. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1056\/NEJMoa1211097","article-title":"A Novel Channelopathy in Pulmonary Arterial Hypertension","volume":"369","author":"Ma","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1161\/CIRCGENETICS.111.961888","article-title":"Whole Exome Sequencing to Identify a Novel Gene (Caveolin-1) Associated with Human Pulmonary Arterial Hypertension","volume":"5","author":"Austin","year":"2012","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1161\/CIRCULATIONAHA.109.916098","article-title":"Epigenetic Attenuation of Mitochondrial Superoxide Dismutase 2 in Pulmonary Arterial Hypertension","volume":"121","author":"Archer","year":"2010","journal-title":"Circulation"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s10863-007-9081-2","article-title":"HIF-1 mediates the Warburg effect in clear cell renal carcinoma","volume":"39","author":"Semenza","year":"2007","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/bph.14932","article-title":"Targeting histone acetylation in pulmonary hypertension and right ventricular hypertrophy","volume":"178","author":"Chelladurai","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.4049\/jimmunol.1100479","article-title":"Emergence of Fibroblasts with a Proinflammatory Epigenetically Altered Phenotype in Severe Hypoxic Pulmonary Hypertension","volume":"187","author":"Li","year":"2011","journal-title":"J. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1161\/CIRCULATIONAHA.112.103176","article-title":"Histone Deacetylation Inhibition in Pulmonary Hypertension","volume":"126","author":"Zhao","year":"2012","journal-title":"Circulation"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1161\/CIRCRESAHA.111.258426","article-title":"Selective Class I Histone Deacetylase Inhibition Suppresses Hypoxia-Induced Cardiopulmonary Remodeling Through an Antiproliferative Mechanism","volume":"110","author":"Cavasin","year":"2012","journal-title":"Circ. Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"e175","DOI":"10.1038\/emm.2015.45","article-title":"Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension","volume":"47","author":"Kim","year":"2015","journal-title":"Exp. Mol. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1161\/CIRCULATIONAHA.114.013339","article-title":"Restoration of Impaired Endothelial Myocyte Enhancer Factor 2 Function Rescues Pulmonary Arterial Hypertension","volume":"131","author":"Kim","year":"2015","journal-title":"Circulation"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.febslet.2015.03.017","article-title":"Promiscuous actions of small molecule inhibitors of the protein kinase D-class IIa HDAC axis in striated muscle","volume":"589","author":"Lemon","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.healun.2012.03.010","article-title":"Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression","volume":"31","author":"Bockmeyer","year":"2012","journal-title":"J. Heart Lung Transplant."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1161\/CIRCRESAHA.109.197491","article-title":"Interleukin-6 Modulates the Expression of the Bone Morphogenic Protein Receptor Type II Through a Novel STAT3\u2013microRNA Cluster 17\/92 Pathway","volume":"104","author":"Brock","year":"2009","journal-title":"Circ. Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1164\/rccm.201106-1093OC","article-title":"Inhibition of MicroRNA-17 Improves Lung and Heart Function in Experimental Pulmonary Hypertension","volume":"185","author":"Pullamsetti","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/nature08195","article-title":"miR-145 and miR-143 regulate smooth muscle cell fate and plasticity","volume":"460","author":"Cordes","year":"2009","journal-title":"Nature"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1161\/CIRCRESAHA.112.267591","article-title":"A Role for miR-145 in Pulmonary Arterial Hypertension","volume":"111","author":"Caruso","year":"2012","journal-title":"Circ. 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