{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:05:36Z","timestamp":1791821136068,"version":"4.3.4"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,1,13]],"date-time":"2017-01-13T00:00:00Z","timestamp":1484265600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,1,13]],"date-time":"2017-01-13T00:00:00Z","timestamp":1484265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Heterozygous germ-line mutations in the bone morphogenetic protein type-II receptor (BMPR-II) gene underlie heritable pulmonary arterial hypertension (HPAH). Although inflammation promotes PAH, the mechanisms by which inflammation and BMPR-II dysfunction conspire to cause disease remain unknown. Here we identify that tumour necrosis factor-\u03b1 (TNF\u03b1) selectively reduces BMPR-II transcription and mediates post-translational BMPR-II cleavage via the sheddases, ADAM10 and ADAM17 in pulmonary artery smooth muscle cells (PASMCs). TNF\u03b1-mediated suppression of BMPR-II subverts BMP signalling, leading to BMP6-mediated PASMC proliferation via preferential activation of an ALK2\/ACTR-IIA signalling axis. Furthermore, TNF\u03b1, via SRC family kinases, increases pro-proliferative NOTCH2 signalling in HPAH PASMCs with reduced BMPR-II expression. We confirm this signalling switch in rodent models of PAH and demonstrate that anti-TNF\u03b1 immunotherapy reverses disease progression, restoring normal BMP\/NOTCH signalling. Collectively, these findings identify mechanisms by which BMP and TNF\u03b1 signalling contribute to disease, and suggest a tractable approach for therapeutic intervention in PAH.<\/jats:p>","DOI":"10.1038\/ncomms14079","type":"journal-article","created":{"date-parts":[[2017,1,13]],"date-time":"2017-01-13T05:05:20Z","timestamp":1484283920000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":235,"title":["TNF\u03b1 drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling"],"prefix":"10.1038","volume":"8","author":[{"given":"Liam A.","family":"Hurst","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Dunmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexi","family":"Crosby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafia","family":"Al-Lamki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Deighton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Southwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marko Z.","family":"Nikolic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth J.","family":"Inman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Bradley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amer A.","family":"Rana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2716-4921","authenticated-orcid":false,"given":"Paul D.","family":"Upton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W.","family":"Morrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,1,13]]},"reference":[{"key":"BFncomms14079_CR1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ccm.2006.11.010","volume":"28","author":"RM Tuder","year":"2007","unstructured":"Tuder, R. M., Marecki, J. C., Richter, A., Fijalkowska, I. & Flores, S. Pathology of pulmonary hypertension. Clin. Chest Med. 28, 23\u201342 vii (2007).","journal-title":"Clin. Chest Med."},{"key":"BFncomms14079_CR2","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/79226","volume":"26","author":"KB Lane","year":"2000","unstructured":"Lane, K. B. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat. Genet. 26, 81\u201384 (2000).","journal-title":"Nat. Genet."},{"key":"BFncomms14079_CR3","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1086\/303059","volume":"67","author":"Z Deng","year":"2000","unstructured":"Deng, Z. et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am. J. Hum. Genet. 67, 737\u2013744 (2000).","journal-title":"Am. J. Hum. Genet."},{"key":"BFncomms14079_CR4","doi-asserted-by":"publisher","first-page":"S32","DOI":"10.1016\/j.jacc.2009.04.015","volume":"54","author":"RD Machado","year":"2009","unstructured":"Machado, R. D. et al. Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 54, S32\u2013S42 (2009).","journal-title":"J. Am. Coll. Cardiol."},{"key":"BFncomms14079_CR5","doi-asserted-by":"publisher","first-page":"1672","DOI":"10.1161\/01.CIR.0000012754.72951.3D","volume":"105","author":"C Atkinson","year":"2002","unstructured":"Atkinson, C. et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105, 1672\u20131678 (2002).","journal-title":"Circulation"},{"key":"BFncomms14079_CR6","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1183\/09031936.00183008","volume":"34","author":"L Dewachter","year":"2009","unstructured":"Dewachter, L. et al. Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension. Eur. Respir. J. 34, 1100\u20131110 (2009).","journal-title":"Eur. Respir. J."},{"key":"BFncomms14079_CR7","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1086\/316947","volume":"68","author":"RD Machado","year":"2001","unstructured":"Machado, R. D. et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am. J. Hum. Genet. 68, 92\u2013102 (2001).","journal-title":"Am. J. Hum. Genet."},{"key":"BFncomms14079_CR8","first-page":"275","volume":"144","author":"RM Tuder","year":"1994","unstructured":"Tuder, R. M., Groves, B., Badesch, D. B. & Voelkel, N. F. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am. J. Pathol. 144, 275\u2013285 (1994).","journal-title":"Am. J. Pathol."},{"key":"BFncomms14079_CR9","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.humpath.2006.11.022","volume":"38","author":"P Dorfmuller","year":"2007","unstructured":"Dorfmuller, P. et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum. Pathol. 38, 893\u2013902 (2007).","journal-title":"Hum. Pathol."},{"key":"BFncomms14079_CR10","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1161\/CIRCULATIONAHA.104.492488","volume":"112","author":"Y Song","year":"2005","unstructured":"Song, Y. et al. Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation 112, 553\u2013562 (2005).","journal-title":"Circulation"},{"key":"BFncomms14079_CR11","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1111\/j.1440-1843.2006.00821.x","volume":"11","author":"T Itoh","year":"2006","unstructured":"Itoh, T. et al. Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension. Respirology 11, 158\u2013163 (2006).","journal-title":"Respirology"},{"key":"BFncomms14079_CR12","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1161\/CIRCULATIONAHA.109.933762","volume":"122","author":"E Soon","year":"2010","unstructured":"Soon, E. et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122, 920\u2013927 (2010).","journal-title":"Circulation"},{"key":"BFncomms14079_CR13","doi-asserted-by":"publisher","first-page":"L39","DOI":"10.1152\/ajplung.2001.280.1.L39","volume":"280","author":"M Fujita","year":"2001","unstructured":"Fujita, M. et al. Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. Am. J. Physiol Lung Cell Mol. Physiol. 280, L39\u2013L49 (2001).","journal-title":"Am. J. Physiol Lung Cell Mol. Physiol."},{"key":"BFncomms14079_CR14","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/aps.2010.187","volume":"32","author":"XQ Li","year":"2011","unstructured":"Li, X. Q. et al. Fluoxetine inhibited extracellular matrix of pulmonary artery and inflammation of lungs in monocrotaline-treated rats. Acta Pharmacol. Sin. 32, 217\u2013222 (2011).","journal-title":"Acta Pharmacol. Sin."},{"key":"BFncomms14079_CR15","doi-asserted-by":"publisher","first-page":"333","DOI":"10.3109\/01902148.2012.702852","volume":"38","author":"D Chen","year":"2012","unstructured":"Chen, D. et al. Atorvastatin prevents dehydromonocrotaline-induced pulmonary hypertension in beagles. Exp. Lung Res. 38, 333\u2013343 (2012).","journal-title":"Exp. Lung Res."},{"key":"BFncomms14079_CR16","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.intimp.2012.08.001","volume":"14","author":"Y Luan","year":"2012","unstructured":"Luan, Y. et al. Mesenchymal stem cell prevention of vascular remodeling in high flow-induced pulmonary hypertension through a paracrine mechanism. Int. Immunopharmacol. 14, 432\u2013437 (2012).","journal-title":"Int. Immunopharmacol."},{"key":"BFncomms14079_CR17","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1111\/1756-185X.12304","volume":"19","author":"LL Zhang","year":"2014","unstructured":"Zhang, L. L., Lu, J., Li, M. T., Wang, Q. & Zeng, X. F. Preventive and remedial application of etanercept attenuate monocrotaline-induced pulmonary arterial hypertension. Int. J. Rheum. Dis. 19, 192\u2013198 (2014).","journal-title":"Int. J. Rheum. Dis."},{"key":"BFncomms14079_CR18","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1089\/jir.2006.26.661","volume":"26","author":"D Mutschler","year":"2006","unstructured":"Mutschler, D. et al. Etanercept reduces late endotoxin-induced pulmonary hypertension in the pig. J. Interferon Cytokine Res. 26, 661\u2013667 (2006).","journal-title":"J. Interferon Cytokine Res."},{"key":"BFncomms14079_CR19","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1161\/ATVBAHA.112.300287","volume":"33","author":"CW Kim","year":"2013","unstructured":"Kim, C. W. et al. Anti-inflammatory and antiatherogenic role of BMP receptor II in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 33, 1350\u20131359 (2013).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"BFncomms14079_CR20","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1093\/jb\/mvp148","volume":"147","author":"K Miyazono","year":"2010","unstructured":"Miyazono, K., Kamiya, Y. & Morikawa, M. Bone morphogenetic protein receptors and signal transduction. J. Biochem. 147, 35\u201351 (2010).","journal-title":"J. Biochem."},{"key":"BFncomms14079_CR21","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1124\/mol.107.041673","volume":"73","author":"PD Upton","year":"2008","unstructured":"Upton, P. D., Long, L., Trembath, R. C. & Morrell, N. W. Functional characterization of bone morphogenetic protein binding sites and Smad1\/5 activation in human vascular cells. Mol. Pharmacol. 73, 539\u2013552 (2008).","journal-title":"Mol. Pharmacol."},{"key":"BFncomms14079_CR22","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1182\/blood-2006-07-034124","volume":"109","author":"L David","year":"2007","unstructured":"David, L., Mallet, C., Mazerbourg, S., Feige, J. J. & Bailly, S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109, 1953\u20131961 (2007).","journal-title":"Blood"},{"key":"BFncomms14079_CR23","doi-asserted-by":"publisher","first-page":"15794","DOI":"10.1074\/jbc.M109.002881","volume":"284","author":"PD Upton","year":"2009","unstructured":"Upton, P. D., Davies, R. J., Trembath, R. C. & Morrell, N. W. Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells. J. Biol. Chem. 284, 15794\u201315804 (2009).","journal-title":"J. Biol. Chem."},{"key":"BFncomms14079_CR24","doi-asserted-by":"publisher","first-page":"2263","DOI":"10.1161\/01.CIR.0000033830.36431.46","volume":"106","author":"G Valdimarsdottir","year":"2002","unstructured":"Valdimarsdottir, G. et al. Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation 106, 2263\u20132270 (2002).","journal-title":"Circulation"},{"key":"BFncomms14079_CR25","doi-asserted-by":"publisher","first-page":"5723","DOI":"10.1093\/nar\/gkg778","volume":"31","author":"T Takizawa","year":"2003","unstructured":"Takizawa, T., Ochiai, W., Nakashima, K. & Taga, T. Enhanced gene activation by Notch and BMP signaling cross-talk. Nucleic Acids Res. 31, 5723\u20135731 (2003).","journal-title":"Nucleic Acids Res."},{"key":"BFncomms14079_CR26","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/nature02006","volume":"425","author":"R Derynck","year":"2003","unstructured":"Derynck, R. & Zhang, Y. E. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425, 577\u2013584 (2003).","journal-title":"Nature"},{"key":"BFncomms14079_CR27","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1165\/rcmb.2005-0103OC","volume":"33","author":"WK Wong","year":"2005","unstructured":"Wong, W. K., Knowles, J. A. & Morse, J. H. Bone morphogenetic protein receptor type II C-terminus interacts with c-Src: implication for a role in pulmonary arterial hypertension. Am. J. Respir. Cell Mol. Biol. 33, 438\u2013446 (2005).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"BFncomms14079_CR28","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1161\/01.RES.0000166926.54293.68","volume":"96","author":"X Yang","year":"2005","unstructured":"Yang, X. et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ. Res. 96, 1053\u20131063 (2005).","journal-title":"Circ. Res."},{"key":"BFncomms14079_CR29","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1161\/CIRCRESAHA.108.173567","volume":"102","author":"J Yang","year":"2008","unstructured":"Yang, J. et al. Mutations in bone morphogenetic protein type II receptor cause dysregulation of id gene expression in pulmonary artery smooth muscle cells. implications for familial pulmonary arterial hypertension. Circ. Res. 102, 1212\u20131221 (2008).","journal-title":"Circ. Res."},{"key":"BFncomms14079_CR30","doi-asserted-by":"publisher","first-page":"24443","DOI":"10.1074\/jbc.M502825200","volume":"280","author":"PB Yu","year":"2005","unstructured":"Yu, P. B., Beppu, H., Kawai, N., Li, E. & Bloch, K. D. Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells. J. Biol. Chem. 280, 24443\u201324450 (2005).","journal-title":"J. Biol. Chem."},{"key":"BFncomms14079_CR31","doi-asserted-by":"publisher","first-page":"3877","DOI":"10.1074\/jbc.M706797200","volume":"283","author":"PB Yu","year":"2008","unstructured":"Yu, P. B. et al. Bone morphogenetic protein (BMP) type II receptor is required for BMP-mediated growth arrest and differentiation in pulmonary artery smooth muscle cells. J. Biol. Chem. 283, 3877\u20133888 (2008).","journal-title":"J. Biol. Chem."},{"key":"BFncomms14079_CR32","doi-asserted-by":"publisher","first-page":"4141","DOI":"10.1158\/0008-5472.CAN-09-4466","volume":"70","author":"LJ Hawinkels","year":"2010","unstructured":"Hawinkels, L. J. et al. Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis. Cancer Res. 70, 4141\u20134150 (2010).","journal-title":"Cancer Res."},{"key":"BFncomms14079_CR33","doi-asserted-by":"publisher","first-page":"7721","DOI":"10.1074\/jbc.M306499200","volume":"279","author":"G Velasco-Loyden","year":"2004","unstructured":"Velasco-Loyden, G., Arribas, J. & Lopez-Casillas, F. The shedding of betaglycan is regulated by pervanadate and mediated by membrane type matrix metalloprotease-1. J. Biol. Chem. 279, 7721\u20137733 (2004).","journal-title":"J. Biol. Chem."},{"key":"BFncomms14079_CR34","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.molcel.2009.06.018","volume":"35","author":"C Liu","year":"2009","unstructured":"Liu, C., Xu, P., Lamouille, S., Xu, J. & Derynck, R. TACE-mediated ectodomain shedding of the type I TGF-beta receptor downregulates TGF-beta signaling. Mol. Cell 35, 26\u201336 (2009).","journal-title":"Mol. Cell"},{"key":"BFncomms14079_CR35","doi-asserted-by":"publisher","first-page":"e54412","DOI":"10.1371\/journal.pone.0054412","volume":"8","author":"M Yoda","year":"2013","unstructured":"Yoda, M. et al. Systemic overexpression of TNFalpha-converting enzyme does not lead to enhanced shedding activity in vivo. PLoS ONE 8, e54412 (2013).","journal-title":"PLoS ONE"},{"key":"BFncomms14079_CR36","doi-asserted-by":"publisher","first-page":"e62721","DOI":"10.1371\/journal.pone.0062721","volume":"8","author":"CE Sanvitale","year":"2013","unstructured":"Sanvitale, C. E. et al. A new class of small molecule inhibitor of BMP signaling. PLoS ONE 8, e62721 (2013).","journal-title":"PLoS ONE"},{"key":"BFncomms14079_CR37","doi-asserted-by":"publisher","first-page":"3390","DOI":"10.1074\/jbc.M114.604397","volume":"290","author":"D Horbelt","year":"2014","unstructured":"Horbelt, D. et al. Small molecules dorsomorphin and LDN-193189 inhibit myostatin\/GDF8 signaling and promote functional myoblast differentiation. J. Biol. Chem. 290, 3390\u20133404 (2014).","journal-title":"J. Biol. Chem."},{"key":"BFncomms14079_CR38","doi-asserted-by":"publisher","first-page":"L1241","DOI":"10.1152\/ajplung.00239.2004","volume":"287","author":"H Beppu","year":"2004","unstructured":"Beppu, H. et al. BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am. J. Physiol. Lung C 287, L1241\u2013L1247 (2004).","journal-title":"Am. J. Physiol. Lung C"},{"key":"BFncomms14079_CR39","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1161\/CIRCULATIONAHA.108.821504","volume":"119","author":"L Long","year":"2009","unstructured":"Long, L. et al. Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease. Circulation 119, 566\u2013576 (2009).","journal-title":"Circulation"},{"key":"BFncomms14079_CR40","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1161\/ATVBAHA.107.141200","volume":"27","author":"RE Morty","year":"2007","unstructured":"Morty, R. E. et al. Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension. Arterioscler. Thromb. Vasc. Biol. 27, 1072\u20131078 (2007).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"BFncomms14079_CR41","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/nm.2021","volume":"15","author":"X Li","year":"2009","unstructured":"Li, X. et al. Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat. Med. 15, 1289\u20131297 (2009).","journal-title":"Nat. Med."},{"key":"BFncomms14079_CR42","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1161\/01.RES.0000044944.99984.25","volume":"91","author":"AH Campos","year":"2002","unstructured":"Campos, A. H., Wang, W., Pollman, M. J. & Gibbons, G. H. Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ. Res. 91, 999\u20131006 (2002).","journal-title":"Circ. Res."},{"key":"BFncomms14079_CR43","doi-asserted-by":"publisher","first-page":"4997","DOI":"10.1182\/blood-2007-08-108597","volume":"111","author":"RC Sainson","year":"2008","unstructured":"Sainson, R. C. et al. TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype. Blood 111, 4997\u20135007 (2008).","journal-title":"Blood"},{"key":"BFncomms14079_CR44","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S1097-2765(00)80417-7","volume":"5","author":"C Brou","year":"2000","unstructured":"Brou, C. et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol. Cell 5, 207\u2013216 (2000).","journal-title":"Mol. Cell"},{"key":"BFncomms14079_CR45","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1016\/j.neuroscience.2007.12.012","volume":"151","author":"A Kurisaki","year":"2008","unstructured":"Kurisaki, A. et al. Activin induces long-lasting N-methyl-D-aspartate receptor activation via scaffolding PDZ protein activin receptor interacting protein 1. Neuroscience 151, 1225\u20131235 (2008).","journal-title":"Neuroscience"},{"key":"BFncomms14079_CR46","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.1161\/CIRCULATIONAHA.109.927681","volume":"121","author":"K Abe","year":"2010","unstructured":"Abe, K. et al. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 121, 2747\u20132754 (2010).","journal-title":"Circulation"},{"key":"BFncomms14079_CR47","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1016\/j.biocel.2006.05.005","volume":"38","author":"W Singhatanadgit","year":"2006","unstructured":"Singhatanadgit, W., Salih, V. & Olsen, I. Bone morphogenetic protein receptors and bone morphogenetic protein signaling are controlled by tumor necrosis factor-alpha in human bone cells. Int. J. Biochem. Cell Biol. 38, 1794\u20131807 (2006).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"BFncomms14079_CR48","doi-asserted-by":"publisher","first-page":"2733","DOI":"10.1161\/ATVBAHA.113.302062","volume":"33","author":"Y Xiao","year":"2013","unstructured":"Xiao, Y., Gong, D. & Wang, W. Soluble JAGGED1 inhibits pulmonary hypertension by attenuating notch signaling. Arterioscler. Thromb. Vasc. Biol. 33, 2733\u20132739 (2013).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"BFncomms14079_CR49","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1242\/dev.126.15.3415","volume":"126","author":"Y Hamada","year":"1999","unstructured":"Hamada, Y. et al. Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development 126, 3415\u20133424 (1999).","journal-title":"Development"},{"key":"BFncomms14079_CR50","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1002\/dvdy.21502","volume":"237","author":"P Varadkar","year":"2008","unstructured":"Varadkar, P. et al. Notch2 is required for the proliferation of cardiac neural crest-derived smooth muscle cells. Dev. Dyn. 237, 1144\u20131152 (2008).","journal-title":"Dev. Dyn."},{"key":"BFncomms14079_CR51","doi-asserted-by":"publisher","first-page":"435","DOI":"10.3109\/01902148.2015.1060545","volume":"41","author":"Y Zhang","year":"2015","unstructured":"Zhang, Y. et al. Inhibition of Notch3 prevents monocrotaline-induced pulmonary arterial hypertension. Exp. Lung Res. 41, 435\u2013443 (2015).","journal-title":"Exp. Lung Res."},{"key":"BFncomms14079_CR52","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1165\/rcmb.2012-0182OC","volume":"48","author":"YR Yu","year":"2013","unstructured":"Yu, Y. R., Mao, L., Piantadosi, C. A. & Gunn, M. D. CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension. Am. J. Respir. Cell Mol. Biol. 48, 647\u2013654 (2013).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"BFncomms14079_CR53","doi-asserted-by":"publisher","first-page":"2730","DOI":"10.1101\/gad.308904","volume":"18","author":"V Domenga","year":"2004","unstructured":"Domenga, V. et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 18, 2730\u20132735 (2004).","journal-title":"Genes Dev."},{"key":"BFncomms14079_CR54","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1139\/o03-077","volume":"82","author":"SM Dehm","year":"2004","unstructured":"Dehm, S. M. & Bonham, K. SRC gene expression in human cancer: the role of transcriptional activation. Biochem. Cell Biol. 82, 263\u2013274 (2004).","journal-title":"Biochem. Cell Biol."},{"key":"BFncomms14079_CR55","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1084\/jem.20111741","volume":"211","author":"H Sawada","year":"2014","unstructured":"Sawada, H. et al. Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J. Exp. Med. 211, 263\u2013280 (2014).","journal-title":"J. Exp. Med."},{"key":"BFncomms14079_CR56","doi-asserted-by":"publisher","first-page":"2695","DOI":"10.1158\/1078-0432.CCR-14-2797","volume":"21","author":"EG Chiorean","year":"2015","unstructured":"Chiorean, E. G. et al. A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors. Clin. Cancer Res. 21, 2695\u20132703 (2015).","journal-title":"Clin. Cancer Res."},{"key":"BFncomms14079_CR57","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/1471-2121-10-20","volume":"10","author":"B Herrera","year":"2009","unstructured":"Herrera, B. & Inman, G. J. A rapid and sensitive bioassay for the simultaneous measurement of multiple bone morphogenetic proteins. Identification and quantification of BMP4, BMP6 and BMP9 in bovine and human serum. BMC Cell Biol. 10, 20 (2009).","journal-title":"BMC Cell Biol."},{"key":"BFncomms14079_CR58","doi-asserted-by":"publisher","first-page":"161","DOI":"10.2174\/1386207053258488","volume":"8","author":"A Ludwig","year":"2005","unstructured":"Ludwig, A. et al. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb. Chem. High Throughput Screen 8, 161\u2013171 (2005).","journal-title":"Comb. Chem. High Throughput Screen"},{"key":"BFncomms14079_CR59","doi-asserted-by":"publisher","first-page":"5578","DOI":"10.1073\/pnas.1017067108","volume":"108","author":"CJ Tape","year":"2011","unstructured":"Tape, C. J. et al. Cross-domain inhibition of TACE ectodomain. Proc. Natl Acad. Sci. USA 108, 5578\u20135583 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms14079_CR60","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1093\/hmg\/11.13.1517","volume":"11","author":"N Rudarakanchana","year":"2002","unstructured":"Rudarakanchana, N. et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum. Mol. Genet. 11, 1517\u20131525 (2002).","journal-title":"Hum. Mol. Genet."},{"key":"BFncomms14079_CR61","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1002\/path.2261","volume":"214","author":"M Southwood","year":"2008","unstructured":"Southwood, M. et al. Regulation of bone morphogenetic protein signalling in human pulmonary vascular development. J. Pathol. 214, 85\u201395 (2008).","journal-title":"J. Pathol."},{"key":"BFncomms14079_CR62","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.4049\/jimmunol.179.2.1264","volume":"179","author":"N Farahi","year":"2007","unstructured":"Farahi, N. et al. Eotaxin-1\/CC chemokine ligand 11: a novel eosinophil survival factor secreted by human pulmonary artery endothelial cells. J. Immunol. 179, 1264\u20131273 (2007).","journal-title":"J. Immunol."},{"key":"BFncomms14079_CR63","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1096\/fj.05-3841com","volume":"19","author":"RS Al-Lamki","year":"2005","unstructured":"Al-Lamki, R. S. et al. TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury. FASEB J. 19, 1637\u20131645 (2005).","journal-title":"FASEB J."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms14079.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms14079","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms14079.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T18:48:29Z","timestamp":1671734909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms14079"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,13]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,4,28]]}},"alternative-id":["BFncomms14079"],"URL":"https:\/\/doi.org\/10.1038\/ncomms14079","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,13]]},"assertion":[{"value":"1 March 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 November 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14079"}}