{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:45:46Z","timestamp":1792179946072,"version":"4.4.0"},"reference-count":27,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T00:00:00Z","timestamp":1565568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CVON","award":["2012-08"],"award-info":[{"award-number":["2012-08"]}]},{"DOI":"10.13039\/501100009480","name":"Stichting Vrienden van het Sophia","doi-asserted-by":"publisher","award":["S13-12, 2012"],"award-info":[{"award-number":["S13-12, 2012"]}],"id":[{"id":"10.13039\/501100009480","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Pulmonary hypertension (PH) as a result of pulmonary vein stenosis (PVS) is extremely difficult to treat. The ideal therapy should not target the high-pressure\/low-flow (HP\/LF) vasculature that drains into stenotic veins, but only the high-pressure\/high-flow (HP\/HF) vasculature draining into unaffected pulmonary veins, reducing vascular resistance and pressure without risk of pulmonary oedema. We aimed to assess the activity of the nitric oxide (NO) pathway in PVS during the development of PH, and investigate whether interventions in the NO pathway differentially affect vasodilation in the HP\/HF vs. HP\/LF territories. Swine underwent pulmonary vein banding (PVB; n = 7) or sham surgery (n = 6) and were chronically instrumented to assess progression of PH. Pulmonary sensitivity to exogenous NO (sodium nitroprusside, SNP) and the contribution of endogenous NO were assessed bi-weekly. The pulmonary vasodilator response to phosphodiesterase-5 (PDE5) inhibition was assessed 12 weeks after PVB or sham surgery. After sacrifice, 12 weeks post-surgery, interventions in the NO pathway on pulmonary small arteries isolated from HP\/LF and HP\/HF territories were further investigated. There were no differences in the in vivo pulmonary vasodilator response to SNP and the pulmonary vasoconstrictor response to endothelial nitric oxide synthase (eNOS) inhibition up to 8 weeks after PVB as compared to the sham group. However, at 10 and 12 weeks post-PVB, the in vivo pulmonary vasodilation in response to SNP was larger in the PVB group. Similarly, the vasoconstriction to eNOS inhibition was larger in the PVB group, particularly during exercise, while pulmonary vasodilation in response to PDE5 inhibition was larger in the PVB group both at rest and during exercise. In isolated pulmonary small arteries, sensitivity to NO donor SNP was similar in PVB vs. sham groups irrespective of HP\/LF and HP\/HF, while sensitivity to the PDE5 inhibitor sildenafil was lower in PVB HP\/HF and sensitivity to bradykinin was lower in PVB HP\/LF. In conclusion, both NO availability and sensitivity were increased in the PVB group. The increased nitric oxide sensitivity was not the result of a decreased PDE5 activity, as PDE5 activity was even increased. Some vasodilators differentially effect HP\/HF vs. HP\/LF vasculature.<\/jats:p>","DOI":"10.3390\/jcm8081204","type":"journal-article","created":{"date-parts":[[2019,8,13]],"date-time":"2019-08-13T04:31:21Z","timestamp":1565670681000},"page":"1204","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis"],"prefix":"10.3390","volume":"8","author":[{"given":"Richard W. B.","family":"van Duin","sequence":"first","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Pediatrics\/Neonatology, Erasmus MC\u2014Sophia Children\u2019s Hospital, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Stam","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Uitterdijk","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrijs","family":"Bartelds","sequence":"additional","affiliation":[{"name":"Division of Paediatric Cardiology, Department of Paediatrics, Erasmus MC\u2014Sophia Children\u2019s Hospital, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-3585","authenticated-orcid":false,"given":"A. H. Jan","family":"Danser","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irwin K. M.","family":"Reiss","sequence":"additional","affiliation":[{"name":"Department of Pediatrics\/Neonatology, Erasmus MC\u2014Sophia Children\u2019s Hospital, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2836-2241","authenticated-orcid":false,"given":"Dirk J.","family":"Duncker","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4852-831X","authenticated-orcid":false,"given":"Daphne","family":"Merkus","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Walter\u2013Brendel Centre of Experimental Medicine, University Hospital, LMU Munich, 80799 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.recesp.2016.01.002","article-title":"2015 ESC\/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension","volume":"69","author":"Galie","year":"2016","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1093\/eurheartj\/ehv512","article-title":"Left ventricular heart failure and pulmonary hypertension","volume":"37","author":"Rosenkranz","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.jacep.2017.05.003","article-title":"Pulmonary Vein Stenosis Following Radiofrequency Ablation of Atrial Fibrillation: Has It Become a Clinically Negligible Complication?","volume":"3","author":"Cappato","year":"2017","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jpeds.2018.02.030","article-title":"Pulmonary Vein Stenosis in Infants: A Systematic Review, Meta-Analysis, and Meta-Regression","volume":"198","author":"Backes","year":"2018","journal-title":"J. Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1136\/hrt.2008.161356","article-title":"Pulmonary vein stenosis: The UK, Ireland and Sweden collaborative study","volume":"95","author":"Seale","year":"2009","journal-title":"Heart"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E90","DOI":"10.1111\/chd.12088","article-title":"Pulmonary vein stenosis with Down syndrome: A rare and frequently fatal cause of pulmonary hypertension in infants and children","volume":"9","author":"Gowda","year":"2014","journal-title":"Congenit. Heart Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1002\/ppul.23679","article-title":"Pulmonary vein stenosis of ex-premature infants with pulmonary hypertension and bronchopulmonary dysplasia, epidemiology, and survival from a multicenter cohort","volume":"52","author":"Mahgoub","year":"2017","journal-title":"Pediatr. Pulmonol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s00246-015-1279-1","article-title":"Pulmonary Hypertension in the Preterm Infant with Chronic Lung Disease can be Caused by Pulmonary Vein Stenosis: A Must-Know Entity","volume":"37","author":"Laux","year":"2016","journal-title":"Pediatr. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1164\/rccm.201503-0529OC","article-title":"Pulmonary Hypertension in Heart Failure. Epidemiology, Right Ventricular Function, and Survival","volume":"192","author":"Gerges","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.jchf.2013.05.001","article-title":"Clinical features, hemodynamics, and outcomes of pulmonary hypertension due to chronic heart failure with reduced ejection fraction: Pulmonary hypertension and heart failure","volume":"1","author":"Miller","year":"2013","journal-title":"JACC Heart Fail."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1164\/rccm.201507-1509ED","article-title":"Progress in Pulmonary Hypertension with Left Heart Failure. Beyond New Definitions and Acronyms","volume":"192","author":"Vanderpool","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1111\/apha.12295","article-title":"Pathophysiology and potential treatments of pulmonary hypertension due to systolic left heart failure","volume":"211","author":"Lundgren","year":"2014","journal-title":"Acta Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1007\/s00247-004-1399-x","article-title":"How is pulmonary arterial blood flow affected by pulmonary venous obstruction in children? A phase-contrast magnetic resonance study","volume":"35","author":"Roman","year":"2005","journal-title":"Pediatr. Radiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"H1204","DOI":"10.1152\/ajpheart.00246.2014","article-title":"Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model","volume":"307","author":"Aguero","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1016\/j.jacc.2013.07.037","article-title":"Noninvasive monitoring of serial changes in pulmonary vascular resistance and acute vasodilator testing using cardiac magnetic resonance","volume":"62","author":"Pereda","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1007\/s12265-014-9564-6","article-title":"Swine model of chronic postcapillary pulmonary hypertension with right ventricular remodeling: Long-term characterization by cardiac catheterization, magnetic resonance, and pathology","volume":"7","author":"Pereda","year":"2014","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1113\/JP275987","article-title":"Transition from post-capillary pulmonary hypertension to combined pre- and post-capillary pulmonary hypertension in swine: A key role for endothelin","volume":"597","author":"Stam","year":"2019","journal-title":"J. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/2049-6958-9-51","article-title":"Experience with exercise right heart catheterization in the diagnosis of pulmonary hypertension: A retrospective study","volume":"9","author":"Keusch","year":"2014","journal-title":"Multidiscip. Respir. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"De Wijs-Meijler, D.P., Stam, K., van Duin, R.W., Verzijl, A., Reiss, I.K., Duncker, D.J., and Merkus, D. (2016). Surgical Placement of Catheters for Long-term Cardiovascular Exercise Testing in Swine. J. Vis. Exp., e53772.","DOI":"10.3791\/53772-v"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"H2198","DOI":"10.1152\/ajpheart.00834.2001","article-title":"Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction","volume":"282","author":"Haitsma","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1161\/01.RES.41.1.19","article-title":"Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats","volume":"41","author":"Mulvany","year":"1977","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"L442","DOI":"10.1152\/ajplung.00057.2013","article-title":"Pulmonary vasoconstrictor influence of endothelin in exercising swine depends critically on phosphodiesterase 5 activity","volume":"306","author":"Zhou","year":"2014","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1161\/CIRCULATIONAHA.107.725481","article-title":"High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury","volume":"117","author":"Moens","year":"2008","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Sykes, M.C., Ireland, C., McSweeney, J.E., Rosenholm, E., Andren, K.G., and Kulik, T.J. (2018). The impact of right ventricular pressure and function on survival in patients with pulmonary vein stenosis. Pulm. Circ., 8.","DOI":"10.1177\/2045894018776894"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00246-017-1780-9","article-title":"Acute Pulmonary Vasodilator Testing and Long-Term Clinical Course in Segmental Pulmonary Vascular Disease","volume":"39","author":"Domingo","year":"2018","journal-title":"Pediatr. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1093\/eurheartj\/ehp297","article-title":"Guidelines for the diagnosis and treatment of pulmonary hypertension: The 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 the International Society of Heart and Lung Transplantation (ISHLT)","volume":"30","author":"Galie","year":"2009","journal-title":"Eur. Heart J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e13159","DOI":"10.14814\/phy2.13159","article-title":"Vascular narrowing in pulmonary arterial hypertension is heterogeneous: Rethinking resistance","volume":"5","author":"Rol","year":"2017","journal-title":"Physiol. Rep."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/8\/1204\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:10:33Z","timestamp":1760188233000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/8\/1204"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,12]]},"references-count":27,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["jcm8081204"],"URL":"https:\/\/doi.org\/10.3390\/jcm8081204","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,12]]}}}