{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:24:27Z","timestamp":1790735067921,"version":"4.1.0"},"reference-count":112,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,22]],"date-time":"2020-11-22T00:00:00Z","timestamp":1606003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI17\/00995"],"award-info":[{"award-number":["PI17\/00995"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The autonomic nervous system (ANS) and renin-angiotensin-aldosterone system (RAAS) are involved in many cardiovascular disorders, including pulmonary hypertension (PH). The current review focuses on the role of the ANS and RAAS activation in PH and updated evidence of potential therapies targeting both systems in this condition, particularly in Groups 1 and 2. State of the art knowledge in preclinical and clinical use of pharmacologic drugs (beta-blockers, beta-three adrenoceptor agonists, or renin-angiotensin-aldosterone signaling drugs) and invasive procedures, such as pulmonary artery denervation, is provided.<\/jats:p>","DOI":"10.3390\/cells9112521","type":"journal-article","created":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T08:18:23Z","timestamp":1606119503000},"page":"2521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Neurohormonal Modulation as a Therapeutic Target in Pulmonary Hypertension"],"prefix":"10.3390","volume":"9","author":[{"given":"In\u00e9s","family":"Garc\u00eda-Lunar","sequence":"first","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain"},{"name":"Hospital Universitario Quir\u00f3nsalud Madrid, UEM, 28223 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red (CIBER) de Enfermedades Cardiovasculares, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Pereda","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red (CIBER) de Enfermedades Cardiovasculares, 28029 Madrid, Spain"},{"name":"Institut Cl\u00ednic Cardiovascular-Hospital Cl\u00ednic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borja","family":"Ibanez","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red (CIBER) de Enfermedades Cardiovasculares, 28029 Madrid, Spain"},{"name":"Department of Cardiology, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1718-2424","authenticated-orcid":false,"given":"Ana","family":"Garc\u00eda-\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red (CIBER) de Enfermedades Cardiovasculares, 28029 Madrid, Spain"},{"name":"Institut Cl\u00ednic Cardiovascular-Hospital Cl\u00ednic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Simonneau, G., Montani, D., Celermajer, D.S., Denton, C.P., Gatzoulis, M.A., Krowka, M., Williams, P.G., and Souza, R. (2019). Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur. Respir. J., 53.","DOI":"10.1183\/13993003.01913-2018"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1183\/09031936.00101211","article-title":"Survival in pulmonary hypertension in Spain: Insights from the Spanish registry","volume":"40","author":"Blanco","year":"2012","journal-title":"Eur. Respir. J."},{"key":"ref_3","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_4","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0735-1097(00)01102-5","article-title":"Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure","volume":"37","author":"Ghio","year":"2001","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/j.healun.2006.06.015","article-title":"Prognostic implications of serial assessments of pulmonary hypertension in severe chronic heart failure","volume":"25","author":"Grigioni","year":"2006","journal-title":"J. Heart Lung Transplant."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Vachiery, J.L., Tedford, R.J., Rosenkranz, S., Palazzini, M., Lang, I., Guazzi, M., Coghlan, G., Chazova, I., and De Marco, T. (2019). Pulmonary hypertension due to left heart disease. Eur. Respir. J., 53.","DOI":"10.1183\/13993003.01897-2018"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s12931-017-0679-6","article-title":"Autonomic nervous system involvement in pulmonary arterial hypertension","volume":"18","author":"Vaillancourt","year":"2017","journal-title":"Respir. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e002569","DOI":"10.1161\/CIRCINTERVENTIONS.115.002569","article-title":"Pulmonary artery denervation reduces pulmonary artery pressure and induces histological changes in an acute porcine model of pulmonary hypertension","volume":"8","author":"Rothman","year":"2015","journal-title":"Circ. Cardiovasc. Interv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1016\/j.jcin.2015.09.015","article-title":"Pulmonary Artery Denervation Attenuates Pulmonary Arterial Remodeling in Dogs with Pulmonary Arterial Hypertension Induced by Dehydrogenized Monocrotaline","volume":"8","author":"Zhou","year":"2015","journal-title":"JACC Cardiovasc. Interv."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rothman, A., Jonas, M., Castel, D., Tzafriri, A.R., Traxler, H., Shav, D., Leon, M.B., Ben-Yehuda, O., and Rubin, L. (2019). Pulmonary Artery Denervation Using Catheter based Ultrasonic Energy. EuroIntervention.","DOI":"10.4244\/EIJ-D-18-01082"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Constantine, A., and Dimopoulos, K. (2020). Pulmonary artery denervation for pulmonary arterial hypertension. Trends Cardiovasc. Med.","DOI":"10.1016\/j.tcm.2020.04.005"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1161\/01.CIR.0000140724.90898.D3","article-title":"Increased sympathetic nerve activity in pulmonary artery hypertension","volume":"110","author":"Ciarka","year":"2004","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1183\/09031936.00145708","article-title":"Impaired cardiac autonomic control relates to disease severity in pulmonary hypertension","volume":"34","author":"Wensel","year":"2009","journal-title":"Eur. Respir. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"R1153","DOI":"10.1152\/ajpregu.00652.2011","article-title":"Cardiac sympathetic activation in patients with pulmonary arterial hypertension","volume":"302","author":"Mak","year":"2012","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1161\/01.CIR.102.16.2005","article-title":"Gene transfer of human prostacyclin synthase ameliorates monocrotaline-induced pulmonary hypertension in rats","volume":"102","author":"Nagaya","year":"2000","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/0735-1097(95)00399-1","article-title":"Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: Relation to hemodynamic variables and endothelin levels","volume":"26","author":"Nootens","year":"1995","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1136\/hrt.63.2.103","article-title":"Ambulatory pulmonary arterial pressure in primary pulmonary hypertension: Variability, relation to systemic arterial pressure, and plasma catecholamines","volume":"63","author":"Richards","year":"1990","journal-title":"Br. Heart J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2045894019868620","DOI":"10.1177\/2045894019868620","article-title":"EXPRESS: Cardiac Sympathetic Dysfunction in Pulmonary Arterial Hypertension: Lesson from Left-sided Heart Failure","volume":"9","author":"Mercurio","year":"2019","journal-title":"Pulm. Circ."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1164\/rccm.200912-1856OC","article-title":"Prognostic significance of sympathetic nervous system activation in pulmonary arterial hypertension","volume":"181","author":"Ciarka","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ijcard.2008.12.087","article-title":"Heart rate variability predicts outcome in children with pulmonary arterial hypertension","volume":"142","author":"Lammers","year":"2010","journal-title":"Int. J. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1164\/rccm.201203-0411OC","article-title":"Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension","volume":"186","author":"Tu","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1164\/rccm.201209-1663PP","article-title":"Neurohormonal axis in patients with pulmonary arterial hypertension: Friend or foe?","volume":"187","author":"Handoko","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nrcardio.2016.163","article-title":"Neurohormonal activation in heart failure with reduced ejection fraction","volume":"14","author":"Hartupee","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1253\/circj.CJ-09-0213","article-title":"Effects of a pure alpha\/beta-adrenergic receptor blocker on monocrotaline-induced pulmonary arterial hypertension with right ventricular hypertrophy in rats","volume":"73","author":"Ishikawa","year":"2009","journal-title":"Circ. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1164\/rccm.201003-0335OC","article-title":"Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats","volume":"182","author":"Bogaard","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1161\/CIRCHEARTFAILURE.111.964494","article-title":"Bisoprolol delays progression towards right heart failure in experimental pulmonary hypertension","volume":"5","author":"Handoko","year":"2012","journal-title":"Circ. Heart Fail."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.jacc.2014.11.050","article-title":"Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension","volume":"65","author":"Perros","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00109-015-1251-9","article-title":"Carvedilol improves biventricular fibrosis and function in experimental pulmonary hypertension","volume":"93","author":"Okumura","year":"2015","journal-title":"J. Mol. Med. (Berl.)"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1183\/09031936.00215514","article-title":"Outcomes of beta-blocker use in pulmonary arterial hypertension: A propensity-matched analysis","volume":"46","author":"Bandyopadhyay","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1164\/rccm.201311-2025LE","article-title":"Treatment of group I pulmonary arterial hypertension with carvedilol is safe","volume":"189","author":"Grinnan","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1136\/thx.2008.111955","article-title":"Pulmonary hypertension: A contraindication to the use of {beta}-adrenoceptor blocking agents","volume":"65","author":"Peacock","year":"2010","journal-title":"Thorax"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1053\/j.gastro.2005.10.013","article-title":"Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension","volume":"130","author":"Provencher","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1161\/CIRCHEARTFAILURE.114.001429","article-title":"beta-blocker therapy is not associated with adverse outcomes in patients with pulmonary arterial hypertension: A propensity score analysis","volume":"7","author":"Thenappan","year":"2014","journal-title":"Circ. Heart Fail."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1183\/13993003.00090-2016","article-title":"Bisoprolol in idiopathic pulmonary arterial hypertension: An explorative study","volume":"48","author":"Allaart","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1016\/j.amjcard.2012.01.368","article-title":"Usefulness of beta-blocker therapy and outcomes in patients with pulmonary arterial hypertension","volume":"109","author":"So","year":"2012","journal-title":"Am. J. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.ijcard.2015.02.033","article-title":"Beta blocker for patients with pulmonary arterial hypertension: A single center experience","volume":"184","author":"Moretti","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Farha, S., Saygin, D., Park, M.M., Cheong, H.I., Asosingh, K., Comhair, S.A., Stephens, O.R., Roach, E.C., Sharp, J., and Highland, K.B. (2017). Pulmonary arterial hypertension treatment with carvedilol for heart failure: A randomized controlled trial. JCI Insight, 2.","DOI":"10.1172\/jci.insight.95240"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2045894019873548","DOI":"10.1177\/2045894019873548","article-title":"Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients","volume":"10","author":"Rijnierse","year":"2020","journal-title":"Pulm. Circ."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/eurheartj\/ehv317","article-title":"2015 ESC\/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)","volume":"37","author":"Galie","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Perros, F., de Man, F.S., Bogaard, H.J., Antigny, F., Simonneau, G., Bonnet, S., Provencher, S., Galie, N., and Humbert, M. (2017). Use of beta-Blockers in Pulmonary Hypertension. Circ. Heart Fail., 10.","DOI":"10.1161\/CIRCHEARTFAILURE.116.003703"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1161\/01.CIR.103.12.1649","article-title":"Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium","volume":"103","author":"Moniotte","year":"2001","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1161\/01.CIR.0000139331.85766.AF","article-title":"Endothelial beta3-adrenoceptors mediate vasorelaxation of human coronary microarteries through nitric oxide and endothelium-dependent hyperpolarization","volume":"110","author":"Dessy","year":"2004","journal-title":"Circulation"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/164_2016_88","article-title":"New and Emerging Therapies and Targets: Beta-3 Agonists","volume":"243","author":"Michel","year":"2017","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1016\/j.jacc.2011.09.033","article-title":"Beta3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation","volume":"58","author":"Aragon","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1007\/s00395-014-0422-0","article-title":"beta3 adrenergic receptor selective stimulation during ischemia\/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes","volume":"109","author":"Pun","year":"2014","journal-title":"Basic Res. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Niu, X., Zhao, L., Li, X., Xue, Y., Wang, B., Lv, Z., Chen, J., Sun, D., and Zheng, Q. (2014). beta3-Adrenoreceptor stimulation protects against myocardial infarction injury via eNOS and nNOS activation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098713"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1161\/CIRCULATIONAHA.113.004940","article-title":"Enhanced expression of beta3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase","volume":"129","author":"Belge","year":"2014","journal-title":"Circulation"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1161\/CIRCULATIONAHA.110.964619","article-title":"beta(3) adrenergic stimulation of the cardiac Na+-K+ pump by reversal of an inhibitory oxidative modification","volume":"122","author":"Bundgaard","year":"2010","journal-title":"Circulation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1093\/eurheartj\/ehx366","article-title":"Cardiac myocyte beta3-adrenergic receptors prevent myocardial fibrosis by modulating oxidant stress-dependent paracrine signaling","volume":"39","author":"Hermida","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/ejhf.714","article-title":"The first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: The BEAT-HF trial","volume":"19","author":"Bundgaard","year":"2017","journal-title":"Eur. J. Heart Fail."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/ehf2.12306","article-title":"Rationale and design of a multicentre, randomized, placebo-controlled trial of mirabegron, a Beta3-adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3-left ventricular hypertrophy (Beta3-LVH)","volume":"5","author":"Pouleur","year":"2018","journal-title":"ESC Heart Fail."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/PL00007650","article-title":"Atypical adrenoceptor-mediated relaxation of canine pulmonary artery through a cyclic adenosine monophosphate-dependent pathway","volume":"177","author":"Tagaya","year":"1999","journal-title":"Lung"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0014-2999(98)00146-0","article-title":"Influence of beta-adrenoceptor agonists on the pulmonary circulation. Effects of a beta3-adrenoceptor antagonist, SR 59230A","volume":"348","author":"Dumas","year":"1998","journal-title":"Eur. J. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00395-016-0567-0","article-title":"Beta-3 adrenergic agonists reduce pulmonary vascular resistance and improve right ventricular performance in a porcine model of chronic pulmonary hypertension","volume":"111","author":"Pereda","year":"2016","journal-title":"Basic Res. Cardiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.jacbts.2020.01.009","article-title":"Design of the beta3-Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure Trial","volume":"5","author":"Blanco","year":"2020","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1139\/cjpp-2015-0431","article-title":"Nebivolol has a beneficial effect in monocrotaline-induced pulmonary hypertension","volume":"94","author":"Pankey","year":"2016","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_58","first-page":"489","article-title":"beta3 adrenergic receptor antagonist SR59230A exerts beneficial effects on right ventricular performance in monocrotaline-induced pulmonary arterial hypertension","volume":"19","author":"Sun","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.bcp.2007.08.012","article-title":"Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system","volume":"75","author":"Lambert","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1161\/hc3401.093155","article-title":"Angiotensin-converting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expression in monocrotaline-induced pulmonary arterial hypertension in rats","volume":"104","author":"Kanno","year":"2001","journal-title":"Circulation"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"L1209","DOI":"10.1152\/ajplung.00144.2001","article-title":"Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF-kappaB and AP-1","volume":"282","author":"Ortiz","year":"2002","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_62","first-page":"1168","article-title":"Angiotensin II and monocrotaline-induced pulmonary hypertension: Effect of losartan (DuP 753), a nonpeptide angiotensin type 1 receptor antagonist","volume":"262","author":"Cassis","year":"1992","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ijcard.2013.08.102","article-title":"A cornerstone of heart failure treatment is not effective in experimental right ventricular failure","volume":"169","author":"Borgdorff","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"H2319","DOI":"10.1152\/ajpheart.00518.2005","article-title":"Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension","volume":"289","author":"Rondelet","year":"2005","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1164\/rccm.200811-1678OC","article-title":"Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension","volume":"179","author":"Ferreira","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1111\/bph.13044","article-title":"Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis","volume":"172","author":"Bruce","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1161\/HYPERTENSIONAHA.114.03871","article-title":"Oral delivery of Angiotensin-converting enzyme 2 and Angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension","volume":"64","author":"Shenoy","year":"2014","journal-title":"Hypertension"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s00408-013-9470-8","article-title":"ACE2 activation confers endothelial protection and attenuates neointimal lesions in prevention of severe pulmonary arterial hypertension in rats","volume":"191","author":"Li","year":"2013","journal-title":"Lung"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Hemnes, A.R., Rathinasabapathy, A., Austin, E.A., Brittain, E.L., Carrier, E.J., Chen, X., Fessel, J.P., Fike, C.D., Fong, P., and Fortune, N. (2018). A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur. Respir. J., 51.","DOI":"10.1183\/13993003.02638-2017"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1161\/CIRCULATIONAHA.112.149534","article-title":"Targeting neurohumoral signaling to treat pulmonary hypertension: The right ventricle coming into focus","volume":"126","author":"Maron","year":"2012","journal-title":"Circulation"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"L678","DOI":"10.1152\/ajplung.00300.2012","article-title":"Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension","volume":"304","author":"Preston","year":"2013","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.amjcard.2013.04.051","article-title":"Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials)","volume":"112","author":"Maron","year":"2013","journal-title":"Am. J. Cardiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1378\/chest.91.3.351","article-title":"Hemodynamic changes with enalapril in pulmonary arterial hypertension secondary to congenital heart disease","volume":"91","author":"Escudero","year":"1987","journal-title":"Chest"},{"key":"ref_74","first-page":"1016","article-title":"Angiotensin converting enzyme inhibitors and pulmonary hypertension","volume":"116","author":"Martiniuc","year":"2012","journal-title":"Rev. Med. Chir. Soc. Med. Nat. Iasi"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3109\/10641969609082610","article-title":"Effect of losartan on right ventricular hypertrophy and cardiac angiotensin I-converting enzyme activity in pulmonary hypertensive rats","volume":"18","author":"Kreutz","year":"1996","journal-title":"Clin. Exp. Hypertens."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/1745-6215-14-91","article-title":"A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: Study protocol for a randomized controlled trial","volume":"14","author":"Elinoff","year":"2013","journal-title":"Trials"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1378\/chest.77.4.525","article-title":"Experimental pulmonary hypertension produced by surgical and chemical denervation of the pulmonary vasculature","volume":"77","author":"Juratsch","year":"1980","journal-title":"Chest"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"269","DOI":"10.4244\/EIJV9I2A43","article-title":"Percutaneous pulmonary artery denervation completely abolishes experimental pulmonary arterial hypertension in vivo","volume":"9","author":"Chen","year":"2013","journal-title":"EuroIntervention"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Liu, C., Jiang, X.M., Zhang, J., Li, B., Li, J., Xie, D.J., and Hu, Z.Y. (2016). Pulmonary artery denervation improves pulmonary arterial hypertension induced right ventricular dysfunction by modulating the local renin-angiotensin-aldosterone system. BMC Cardiovasc. Disord., 16.","DOI":"10.1186\/s12872-016-0366-4"},{"key":"ref_80","unstructured":"Hang, Z., Wande, Y., and Shaoliang, C. (2018). EXPRESS: Pulmonary artery denervation improves hemodynamics and cardiac function in pulmonary hypertension secondary to heart failure. Pulm. Circ., 2045894018816297."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00395-018-0714-x","article-title":"Effect of pulmonary artery denervation in postcapillary pulmonary hypertension: Results of a randomized controlled translational study","volume":"114","author":"Pereda","year":"2019","journal-title":"Basic Res. Cardiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1161\/ATVBAHA.118.311992","article-title":"Transthoracic Pulmonary Artery Denervation for Pulmonary Arterial Hypertension","volume":"39","author":"Huang","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.jacc.2013.05.075","article-title":"Pulmonary artery denervation to treat pulmonary arterial hypertension: The single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension)","volume":"62","author":"Chen","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e002837","DOI":"10.1161\/CIRCINTERVENTIONS.115.002837","article-title":"Hemodynamic, functional, and clinical responses to pulmonary artery denervation in patients with pulmonary arterial hypertension of different causes: Phase II results from the Pulmonary Artery Denervation-1 study","volume":"8","author":"Chen","year":"2015","journal-title":"Circ. Cardiovasc. Interv."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.jcin.2018.09.021","article-title":"Pulmonary Artery Denervation Significantly Increases 6-Min Walk Distance for Patients with Combined Pre- and Post-Capillary Pulmonary Hypertension Associated With Left Heart Failure: The PADN-5 Study","volume":"12","author":"Zhang","year":"2019","journal-title":"JACC Cardiovasc. Interv."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.jacc.2020.06.064","article-title":"Pulmonary Artery Denervation for Patients with Residual Pulmonary Hypertension After Pulmonary Endarterectomy","volume":"76","author":"Romanov","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.jcin.2019.12.027","article-title":"Intravascular Ultrasound Pulmonary Artery Denervation to Treat Pulmonary Arterial Hypertension (TROPHY1): Multicenter, Early Feasibility Study","volume":"13","author":"Rothman","year":"2020","journal-title":"JACC Cardiovasc. Interv."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.recesp.2014.11.025","article-title":"Beneficial Effects of Renal Denervation on Pulmonary Vascular Remodeling in Experimental Pulmonary Artery Hypertension","volume":"68","author":"Qingyan","year":"2015","journal-title":"Rev. Esp. Cardiol. (Engl. Ed.)"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"46846","DOI":"10.18632\/oncotarget.15154","article-title":"Effects of renal denervation on monocrotaline induced pulmonary remodeling","volume":"8","author":"Liu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jacbts.2016.09.007","article-title":"Renal Denervation Reduces Pulmonary Vascular Remodeling and Right Ventricular Diastolic Stiffness in Experimental Pulmonary Hypertension","volume":"2","author":"Happe","year":"2017","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1161\/HYPERTENSIONAHA.113.01979","article-title":"Cervical ganglion block attenuates the progression of pulmonary hypertension via nitric oxide and arginase pathways","volume":"63","author":"Na","year":"2014","journal-title":"Hypertension"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s12931-019-1090-2","article-title":"Transection of the cervical sympathetic trunk inhibits the progression of pulmonary arterial hypertension via ERK-1\/2 Signalling","volume":"20","author":"Zhao","year":"2019","journal-title":"Respir. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1111\/joic.12343","article-title":"Anatomic Patterns of Renal Arterial Sympathetic Innervation: New Aspects for Renal Denervation","volume":"29","author":"Imnadze","year":"2016","journal-title":"J. Interv. Cardiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/ejhf.192","article-title":"Pulmonary arterial capacitance in patients with heart failure and reactive pulmonary hypertension","volume":"17","author":"Dragu","year":"2015","journal-title":"Eur. J. Heart Fail."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1093\/eurheartj\/ehx700","article-title":"Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: A multicenter, double-blind, randomized clinical trial","volume":"39","author":"Bermejo","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.jcin.2018.10.045","article-title":"Pulmonary Artery Denervation: A New, Long-Awaited Interventional Treatment for Combined Pre- and Post-Capillary Pulmonary Hypertension?","volume":"12","author":"Dimopoulos","year":"2019","journal-title":"JACC Cardiovasc. Interv."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Fujisawa, T., Kataoka, M., Kawakami, T., Isobe, S., Nakajima, K., Kunitomi, A., Kashimura, S., Katsumata, Y., Nishiyama, T., and Kimura, T. (2017). Pulmonary Artery Denervation by Determining Targeted Ablation Sites for Treatment of Pulmonary Arterial Hypertension. Circ. Cardiovasc. Interv., 10.","DOI":"10.1161\/CIRCINTERVENTIONS.117.005812"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Condori Leandro, H.I., Vakhrushev, A.D., Goncharova, N.S., Korobchenko, L.E., Koshevaya, E.G., Mitrofanova, L.B., Andreeva, E.M., Moiseeva, O.M., Lebedev, D.S., and Mikhaylov, E.N. (2020). Stimulation Mapping of the Pulmonary Artery for Denervation Procedures: An Experimental Study. J. Cardiovasc. Transl. Res.","DOI":"10.1093\/eurheartj\/ehab724.3423"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1016\/j.jcin.2015.10.022","article-title":"Pulmonary Artery Denervation for Pulmonary Artery Hypertension","volume":"8","author":"Rubin","year":"2015","journal-title":"JACC Cardiovasc. Interv."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e001813","DOI":"10.1161\/CIRCINTERVENTIONS.114.001813","article-title":"Comparison of histopathologic analysis following renal sympathetic denervation over multiple time points","volume":"8","author":"Sakakura","year":"2015","journal-title":"Circ. Cardiovasc. Interv."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"35","DOI":"10.18087\/cardio.2020.1.n771","article-title":"Circular Sympathetic Pulmonary Artery Denervation in Cardiac Surgery Patients with Mitral Valve Defect, Atrial Fibrillation and High Pulmonary Hypertension","volume":"60","author":"Trofimov","year":"2020","journal-title":"Kardiologiia"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.jacc.2013.06.032","article-title":"New treatment strategies for pulmonary arterial hypertension: Hopes or hypes?","volume":"62","author":"Galie","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e003422","DOI":"10.1161\/CIRCINTERVENTIONS.115.003422","article-title":"Letter by Hoeper and Galie Regarding Article, \u201cHemodynamic, Functional, and Clinical Responses to Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension of Different Causes: Phase II Results From the Pulmonary Artery Denervation-1 Study\u201d","volume":"9","author":"Hoeper","year":"2016","journal-title":"Circ. Cardiovasc. Interv."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"659","DOI":"10.4244\/EIJV15I8A122","article-title":"Pulmonary artery denervation\u2014The time has come for a multicentre blinded randomised controlled trial","volume":"15","author":"Lang","year":"2019","journal-title":"EuroIntervention"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.jcin.2019.02.015","article-title":"Will Pulmonary Artery Denervation Really Have a Place in the Armamentarium of the Pulmonary Hypertension Specialist?","volume":"12","author":"Yaylali","year":"2019","journal-title":"JACC Cardiovasc. Interv."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1056\/NEJMoa1402670","article-title":"A controlled trial of renal denervation for resistant hypertension","volume":"370","author":"Bhatt","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1016\/S0140-6736(10)62039-9","article-title":"Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial","volume":"376","author":"Symplicity","year":"2010","journal-title":"Lancet"},{"key":"ref_108","first-page":"551","article-title":"Catheter-based Renal Denervation as a Treatment for Pulmonary Hypertension: Hope or Hype?","volume":"68","author":"Badimon","year":"2015","journal-title":"Rev. Esp. Cardiol. (Engl. Ed.)"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.jacep.2017.06.006","article-title":"Efficacy of Stellate Ganglion Blockade in Managing Electrical Storm: A Systematic Review","volume":"3","author":"Meng","year":"2017","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1161\/CIRCULATIONAHA.117.027451","article-title":"Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension","volume":"137","author":"Kurakula","year":"2018","journal-title":"Circulation"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.jchf.2015.05.008","article-title":"Novel Interventional Therapies to Modulate the Autonomic Tone in Heart Failure","volume":"3","author":"Chatterjee","year":"2015","journal-title":"JACC Heart Fail."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.jacbts.2018.07.007","article-title":"Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats with Severe Pulmonary Arterial Hypertension","volume":"3","author":"Yoshida","year":"2018","journal-title":"JACC Basic Transl. Sci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/11\/2521\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:35:35Z","timestamp":1760178935000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/11\/2521"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,22]]},"references-count":112,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["cells9112521"],"URL":"https:\/\/doi.org\/10.3390\/cells9112521","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,22]]}}}