{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T03:54:24Z","timestamp":1792295664630,"version":"4.4.0"},"reference-count":30,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2013,5,22]],"date-time":"2013-05-22T00:00:00Z","timestamp":1369180800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2013,8]]},"abstract":"<jats:title>New Findings<\/jats:title><jats:p><jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p><jats:bold>What is the topic of this review?<\/jats:bold><\/jats:p><jats:p>This review summarises our current knowledge of dysregulated bone morphogenetic protein (BMP) and transforming growth factor\u2010\u03b2<jats:sub>1<\/jats:sub> (TGF\u03b2<jats:sub>1<\/jats:sub>) signalling in pulmonary arterial hypertension.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:bold>What advances does it highlight?<\/jats:bold><\/jats:p><jats:p>Reduced expression of the bone morphogenetic protein (BMP) type II receptor is common to the monocrotaline (MCT\u2010PAH) and hypoxic rat models of pulmonary hypertension (PH). However, reduced BMP signalling and enhanced transforming growth factor\u2010\u03b2<jats:sub>1<\/jats:sub> (TGF\u03b2<jats:sub>1<\/jats:sub>) signalling is observed only in MCT\u2010PAH. Furthermore, TGF\u03b2<jats:sub>1<\/jats:sub> receptor blockade blocks MCT\u2010PAH, but not hypoxic PH. Transforming growth factor\u2010\u03b2<jats:sub>1<\/jats:sub> inhibits BMP signalling in pulmonary artery smooth muscle cells.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p>Germ\u2010line mutations in the bone morphogenetic protein type II receptor (<jats:italic>BMPR2<\/jats:italic>; BMPR\u2010II) gene, a transforming growth factor\u2010\u03b2 (TGF\u03b2) receptor superfamily member, cause the majority of cases of heritable pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension is a subset of pulmonary hypertension (PH) disorders, which also encompass hypoxia\u2010related lung diseases. Bone morphogenetic proteins (BMPs), via BMPR\u2010II, activate the canonical Smad1\/5\/9 pathway, whereas TGF\u03b2s (TGF\u03b21\u20133) activate the Smad2\/3 pathway via the ALK5 receptor. Dysregulated TGF\u03b2<jats:sub>1<\/jats:sub> signalling is pathogenic in fibrotic diseases. We compared two rat PH models, monocrotaline\u2010induced PAH (MCT\u2010PAH) and chronic normobaric hypoxia (fractional inspired O<jats:sub>2<\/jats:sub> 10%), to address whether BMPR\u2010II loss is common to PH and permits pathogenic TGF\u03b2<jats:sub>1<\/jats:sub> signalling. Both models exhibited reduced lung BMPR\u2010II expression, but increased TGF\u03b2<jats:sub>1<\/jats:sub> signalling and decreased BMP signalling were observed only in MCT\u2010PAH. Furthermore, a pharmacological ALK5 inhibitor prevented disease progression in the MCT\u2010PAH model, but not in hypoxia. <jats:italic>In vitro<\/jats:italic> studies using human pulmonary artery smooth muscle cells showed that TGF\u03b2<jats:sub>1<\/jats:sub> directly inhibits BMP\u2013Smad signalling. In conclusion, BMPR\u2010II loss is common to the hypoxic and MCT\u2010PAH models, but systemic ALK5 inhibition is effective only in the MCT model, highlighting a specific role for TGF\u03b2<jats:sub>1<\/jats:sub> in vascular remodelling in MCT\u2010PAH, potentially via direct inhibition of BMP signalling.<\/jats:p>","DOI":"10.1113\/expphysiol.2012.069104","type":"journal-article","created":{"date-parts":[[2013,5,4]],"date-time":"2013-05-04T04:24:41Z","timestamp":1367641481000},"page":"1262-1266","source":"Crossref","is-referenced-by-count":45,"title":["The transforming growth factor\u2010\u03b2\u2013bone morphogenetic protein type signalling pathway in pulmonary vascular homeostasis and disease"],"prefix":"10.1113","volume":"98","author":[{"given":"Paul D.","family":"Upton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W.","family":"Morrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,5,22]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2000.278.5.L981"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00534.2009"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.847707"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000012754.72951.3D"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.128.6_suppl.585S"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/1753465810379801"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00309.2011"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.03.00038903"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00034.2007"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.199158"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.736801"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00171.2005"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111023200"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.821504"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000215809.47923.fd"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-011-1275-6"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00866.2009"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.04.015"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00309.2006"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/hc3201.094152"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.141200"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21605"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-11-85"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00020.2006"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.04.012"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00206.2005"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080565"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.128.6_suppl.553S"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000166926.54293.68"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200707-1083OC"}],"container-title":["Experimental Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2Fexpphysiol.2012.069104","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/expphysiol.2012.069104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T16:47:38Z","timestamp":1697647658000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/expphysiol.2012.069104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,5,22]]},"references-count":30,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2013,8]]}},"alternative-id":["10.1113\/expphysiol.2012.069104"],"URL":"https:\/\/doi.org\/10.1113\/expphysiol.2012.069104","archive":["Portico"],"relation":{},"ISSN":["0958-0670","1469-445X"],"issn-type":[{"value":"0958-0670","type":"print"},{"value":"1469-445X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,5,22]]}}}