{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T04:13:34Z","timestamp":1789791214380,"version":"4.0.1"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,30]],"date-time":"2017-05-30T00:00:00Z","timestamp":1496102400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,30]],"date-time":"2017-05-30T00:00:00Z","timestamp":1496102400000},"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><jats:p>Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-\u03b2 signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-\u03b2 blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-\u03b2 is regulated at the level of activation, but how TGF-\u03b2 is activated in this disease is unknown. Here we show TGF-\u03b2 activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in<jats:italic>Schistosoma<\/jats:italic>-exposed mice. Following<jats:italic>Schistosoma<\/jats:italic>exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-\u03b2 activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-\u03b2 could thus be a therapeutic approach in TGF-\u03b2-dependent vascular diseases.<\/jats:p>","DOI":"10.1038\/ncomms15494","type":"journal-article","created":{"date-parts":[[2017,5,30]],"date-time":"2017-05-30T10:26:13Z","timestamp":1496139973000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":140,"title":["TGF-\u03b2 activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension"],"prefix":"10.1038","volume":"8","author":[{"given":"Rahul","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Mickael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biruk","family":"Kassa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Gebreab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey C.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Koyanagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Sanders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Barthel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Meadows","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Irwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. Alexandre","family":"McKeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzette","family":"Riddle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Dale Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie E.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Hernandez-Saavedra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Bandeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Maloney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd M.","family":"Bull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Janssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt R.","family":"Stenmark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubin M.","family":"Tuder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian B.","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,30]]},"reference":[{"key":"BFncomms15494_CR1","doi-asserted-by":"publisher","first-page":"D34","DOI":"10.1016\/j.jacc.2013.10.029","volume":"62","author":"G Simonneau","year":"2013","unstructured":"Simonneau, G. et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 62, D34\u2013D41 (2013).","journal-title":"J. Am. Coll. Cardiol."},{"key":"BFncomms15494_CR2","doi-asserted-by":"publisher","first-page":"D4","DOI":"10.1016\/j.jacc.2013.10.025","volume":"62","author":"RM Tuder","year":"2013","unstructured":"Tuder, R. M. et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J. Am. Coll. Cardiol. 62, D4\u201312 (2013).","journal-title":"J. Am. Coll. Cardiol."},{"key":"BFncomms15494_CR3","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1161\/CIRCULATIONAHA.113.003072","volume":"128","author":"BB Graham","year":"2013","unstructured":"Graham, B. B. et al. Transforming growth factor-\u03b2 signaling promotes pulmonary hypertension caused by Schistosoma mansoni. Circulation 128, 1354\u20131364 (2013).","journal-title":"Circulation"},{"key":"BFncomms15494_CR4","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1164\/rccm.200311-1602OC","volume":"170","author":"A Richter","year":"2004","unstructured":"Richter, A. et al. Impaired transforming growth factor-beta signaling in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 170, 1340\u20131348 (2004).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"BFncomms15494_CR5","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. Nat. Genet. 26, 81\u201384 (2000).","journal-title":"Nat. Genet."},{"key":"BFncomms15494_CR6","doi-asserted-by":"publisher","first-page":"4548","DOI":"10.1172\/JCI57734","volume":"121","author":"W Ma","year":"2011","unstructured":"Ma, W. et al. Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease. J. Clin. Invest. 121, 4548\u20134566 (2011).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15494_CR7","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1164\/rccm.200707-1083OC","volume":"177","author":"AL Zaiman","year":"2008","unstructured":"Zaiman, A. L. et al. Role of the TGF-beta\/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. Am. J. Respir. Crit. Care Med. 177, 896\u2013905 (2008).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"BFncomms15494_CR8","doi-asserted-by":"publisher","first-page":"2795","DOI":"10.1172\/JCI77958","volume":"125","author":"LM Rice","year":"2015","unstructured":"Rice, L. M. et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J. Clin. Invest. 125, 2795\u20132807 (2015).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15494_CR9","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s00262-015-1653-0","volume":"64","author":"ME Lacouture","year":"2015","unstructured":"Lacouture, M. E. et al. Cutaneous keratoacanthomas\/squamous cell carcinomas associated with neutralization of transforming growth factor \u03b2 by the monoclonal antibody fresolimumab (GC1008). Cancer Immunol. Immunother 64, 437\u2013446 (2015).","journal-title":"Cancer Immunol. Immunother"},{"key":"BFncomms15494_CR10","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1146\/annurev-immunol-032713-120257","volume":"32","author":"MA Travis","year":"2014","unstructured":"Travis, M. A. & Sheppard, D. TGF-\u03b2 activation and function in immunity. Annu. Rev. Immunol. 32, 51\u201382 (2014).","journal-title":"Annu. Rev. Immunol."},{"key":"BFncomms15494_CR11","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.cytogfr.2013.06.003","volume":"24","author":"IB Robertson","year":"2013","unstructured":"Robertson, I. B. & Rifkin, D. B. Unchaining the beast; insights from structural and evolutionary studies on TGF\u03b2 secretion, sequestration, and activation. Cytokine Growth Factor Rev. 24, 355\u2013372 (2013).","journal-title":"Cytokine Growth Factor Rev."},{"key":"BFncomms15494_CR12","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1016\/S0092-8674(00)81460-9","volume":"93","author":"SE Crawford","year":"1998","unstructured":"Crawford, S. E. et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 93, 1159\u20131170 (1998).","journal-title":"Cell"},{"key":"BFncomms15494_CR13","doi-asserted-by":"publisher","first-page":"13586","DOI":"10.1074\/jbc.274.19.13586","volume":"274","author":"SM Ribeiro","year":"1999","unstructured":"Ribeiro, S. M., Poczatek, M., Schultz-Cherry, S., Villain, M. & Murphy-Ullrich, J. E. The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta. J. Biol. Chem. 274, 13586\u201313593 (1999).","journal-title":"J. Biol. Chem."},{"key":"BFncomms15494_CR14","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/nature01413","volume":"422","author":"DG Morris","year":"2003","unstructured":"Morris, D. G. et al. Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema. Nature 422, 169\u2013173 (2003).","journal-title":"Nature"},{"key":"BFncomms15494_CR15","doi-asserted-by":"crossref","first-page":"26783","DOI":"10.1016\/S0021-9258(18)47087-1","volume":"269","author":"S Schultz-Cherry","year":"1994","unstructured":"Schultz-Cherry, S., Lawler, J. & Murphy-Ullrich, J. E. The type 1 repeats of thrombospondin 1 activate latent transforming growth factor-beta. J. Biol. Chem. 269, 26783\u201326788 (1994).","journal-title":"J. Biol. Chem."},{"key":"BFncomms15494_CR16","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.matbio.2014.05.003","volume":"37","author":"DR Soto-Pantoja","year":"2014","unstructured":"Soto-Pantoja, D. R. et al. Thrombospondin-1 and CD47 signaling regulate healing of thermal injury in mice. Matrix Biol. J. Int. Soc. Matrix Biol. 37, 25\u201334 (2014).","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol."},{"key":"BFncomms15494_CR17","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1093\/cvr\/cvv243","volume":"109","author":"D Labrousse-Arias","year":"2016","unstructured":"Labrousse-Arias, D. et al. HIF-2\u03b1-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction. Cardiovasc. Res. 109, 115\u2013130 (2016).","journal-title":"Cardiovasc. Res."},{"key":"BFncomms15494_CR18","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1093\/cvr\/cvr356","volume":"93","author":"PM Bauer","year":"2012","unstructured":"Bauer, P. M. et al. Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1. Cardiovasc. Res. 93, 682\u2013693 (2012).","journal-title":"Cardiovasc. Res."},{"key":"BFncomms15494_CR19","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/1749-8090-5-32","volume":"5","author":"CD Ochoa","year":"2010","unstructured":"Ochoa, C. D., Yu, L., Al-Ansari, E., Hales, C. A. & Quinn, D. A. Thrombospondin-1 null mice are resistant to hypoxia-induced pulmonary hypertension. J. Cardiothorac. Surg. 5, 32 (2010).","journal-title":"J. Cardiothorac. Surg."},{"key":"BFncomms15494_CR20","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.matbio.2014.01.012","volume":"37","author":"A Resovi","year":"2014","unstructured":"Resovi, A., Pinessi, D., Chiorino, G. & Taraboletti, G. Current understanding of the thrombospondin-1 interactome. Matrix Biol. J. Int. Soc. Matrix Biol. 37, 83\u201391 (2014).","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol."},{"key":"BFncomms15494_CR21","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/cvr\/cvw218","volume":"113","author":"NM Rogers","year":"2017","unstructured":"Rogers, N. M. et al. TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction. Cardiovasc. Res. 113, 15\u201329 (2017).","journal-title":"Cardiovasc. Res."},{"key":"BFncomms15494_CR22","doi-asserted-by":"publisher","first-page":"L541","DOI":"10.1152\/ajplung.00282.2011","volume":"302","author":"JP Maloney","year":"2012","unstructured":"Maloney, J. P. et al. Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 302, L541\u2013L554 (2012).","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"BFncomms15494_CR23","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1172\/JCI34261","volume":"118","author":"PJ Hotez","year":"2008","unstructured":"Hotez, P. J. et al. Helminth infections: the great neglected tropical diseases. J. Clin. Invest. 118, 1311\u20131321 (2008).","journal-title":"J. Clin. Invest."},{"key":"BFncomms15494_CR24","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.2353\/ajpath.2010.100063","volume":"177","author":"BB Graham","year":"2010","unstructured":"Graham, B. B. et al. Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am. J. Pathol. 177, 1549\u20131561 (2010).","journal-title":"Am. J. Pathol."},{"key":"BFncomms15494_CR25","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1164\/rccm.201410-1820OC","volume":"192","author":"R Kumar","year":"2015","unstructured":"Kumar, R. et al. The causal role of IL-4 and IL-13 in Schistosoma mansoni pulmonary hypertension. Am. J. Respir. Crit. Care Med. 192, 998\u20131008 (2015).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"BFncomms15494_CR26","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/sj.icb.7100014","volume":"85","author":"MS Wilson","year":"2007","unstructured":"Wilson, M. S. et al. Immunopathology of schistosomiasis. Immunol. Cell Biol. 85, 148\u2013154 (2007).","journal-title":"Immunol. Cell Biol."},{"key":"BFncomms15494_CR27","doi-asserted-by":"publisher","first-page":"e1004282","DOI":"10.1371\/journal.ppat.1004282","volume":"10","author":"M Nascimento","year":"2014","unstructured":"Nascimento, M. et al. Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis. PLoS Pathog. 10, e1004282 (2014).","journal-title":"PLoS Pathog."},{"key":"BFncomms15494_CR28","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1084\/jem.20070075","volume":"204","author":"L Arnold","year":"2007","unstructured":"Arnold, L. et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med. 204, 1057\u20131069 (2007).","journal-title":"J. Exp. Med."},{"key":"BFncomms15494_CR29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1182\/blood.V65.1.79.79","volume":"65","author":"EA Jaffe","year":"1985","unstructured":"Jaffe, E. A., Ruggiero, J. T. & Falcone, D. J. Monocytes and macrophages synthesize and secrete thrombospondin. Blood 65, 79\u201384 (1985).","journal-title":"Blood"},{"key":"BFncomms15494_CR30","doi-asserted-by":"publisher","first-page":"2573","DOI":"10.1016\/j.ajpath.2011.02.039","volume":"178","author":"A Lu","year":"2011","unstructured":"Lu, A., Miao, M., Schoeb, T. R., Agarwal, A. & Murphy-Ullrich, J. E. Blockade of TSP1-dependent TGF-\u03b2 activity reduces renal injury and proteinuria in a murine model of diabetic nephropathy. Am. J. Pathol. 178, 2573\u20132586 (2011).","journal-title":"Am. J. Pathol."},{"key":"BFncomms15494_CR31","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1006\/abio.1994.1042","volume":"216","author":"M Abe","year":"1994","unstructured":"Abe, M. et al. An assay for transforming growth factor-beta using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Anal. Biochem. 216, 276\u2013284 (1994).","journal-title":"Anal. Biochem."},{"key":"BFncomms15494_CR32","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1111\/j.1743-6109.2006.00158.x","volume":"14","author":"W-Y Li","year":"2006","unstructured":"Li, W.-Y. et al. Transforming growth factor-beta3 affects plasminogen activator inhibitor-1 expression in fetal mice and modulates fibroblast-mediated collagen gel contraction. Wound Repair Regen. 14, 516\u2013525 (2006).","journal-title":"Wound Repair Regen."},{"key":"BFncomms15494_CR33","doi-asserted-by":"crossref","first-page":"3905","DOI":"10.1242\/jcs.114.21.3905","volume":"114","author":"SM Kutz","year":"2001","unstructured":"Kutz, S. M., Hordines, J., McKeown-Longo, P. J. & Higgins, P. J. TGF-beta1-induced PAI-1 gene expression requires MEK activity and cell-to-substrate adhesion. J. Cell Sci. 114, 3905\u20133914 (2001).","journal-title":"J. Cell Sci."},{"key":"BFncomms15494_CR34","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/S0014-4835(03)00220-3","volume":"77","author":"R Fuchshofer","year":"2003","unstructured":"Fuchshofer, R., Welge-Lussen, U. & L\u00fctjen-Drecoll, E. The effect of TGF-beta2 on human trabecular meshwork extracellular proteolytic system. Exp. Eye Res. 77, 757\u2013765 (2003).","journal-title":"Exp. Eye Res."},{"key":"BFncomms15494_CR35","doi-asserted-by":"crossref","first-page":"7741","DOI":"10.1016\/S0021-9258(18)68561-8","volume":"263","author":"E Van Obberghen-Schilling","year":"1988","unstructured":"Van Obberghen-Schilling, E., Roche, N. S., Flanders, K. C., Sporn, M. B. & Roberts, A. B. Transforming growth factor beta 1 positively regulates its own expression in normal and transformed cells. J. Biol. Chem. 263, 7741\u20137746 (1988).","journal-title":"J. Biol. Chem."},{"key":"BFncomms15494_CR36","doi-asserted-by":"publisher","first-page":"3004","DOI":"10.1002\/art.39287","volume":"67","author":"LM Rice","year":"2015","unstructured":"Rice, L. M. et al. A longitudinal biomarker for the extent of skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 67, 3004\u20133015 (2015).","journal-title":"Arthritis Rheumatol."},{"key":"BFncomms15494_CR37","first-page":"2565","volume":"29","author":"RF Macko","year":"2002","unstructured":"Macko, R. F. et al. Increased circulating concentrations of the counteradhesive proteins SPARC and thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet and endothelial cell activation. J. Rheumatol. 29, 2565\u20132570 (2002).","journal-title":"J. Rheumatol."},{"key":"BFncomms15494_CR38","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1186\/s12931-016-0412-x","volume":"17","author":"R Kaiser","year":"2016","unstructured":"Kaiser, R., Frantz, C., Bals, R. & Wilkens, H. The role of circulating thrombospondin-1 in patients with precapillary pulmonary hypertension. Respir. Res. 17, 96 (2016).","journal-title":"Respir. Res."},{"key":"BFncomms15494_CR39","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1084\/jem.20150900","volume":"213","author":"T Shirai","year":"2016","unstructured":"Shirai, T. et al. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J. Exp. Med. 213, 337\u2013354 (2016).","journal-title":"J. Exp. Med."},{"key":"BFncomms15494_CR40","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1074\/jbc.M114.618421","volume":"290","author":"T Bancroft","year":"2015","unstructured":"Bancroft, T. et al. Up-regulation of thrombospondin-2 in Akt1-null mice contributes to compromised tissue repair due to abnormalities in fibroblast function. J. Biol. Chem. 290, 409\u2013422 (2015).","journal-title":"J. Biol. Chem."},{"key":"BFncomms15494_CR41","doi-asserted-by":"publisher","first-page":"e83846","DOI":"10.1371\/journal.pone.0083846","volume":"8","author":"C Daniel","year":"2013","unstructured":"Daniel, C., Vogelbacher, R., Stief, A., Grigo, C. & Hugo, C. Long-term gene therapy with thrombospondin 2 inhibits TGF-\u03b2 activation, inflammation and angiogenesis in chronic allograft nephropathy. PLoS ONE 8, e83846 (2013).","journal-title":"PLoS ONE"},{"key":"BFncomms15494_CR42","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1161\/CIRCRESAHA.117.305262","volume":"117","author":"Z Liu","year":"2015","unstructured":"Liu, Z. et al. Thrombospondin-1 (TSP1) contributes to the development of vascular inflammation by regulating monocytic cell motility in mouse models of abdominal aortic aneurysm. Circ. Res. 117, 129\u2013141 (2015).","journal-title":"Circ. Res."},{"key":"BFncomms15494_CR43","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.ijcard.2013.04.139","volume":"168","author":"SM Krishna","year":"2013","unstructured":"Krishna, S. M. & Golledge, J. The role of thrombospondin-1 in cardiovascular health and pathology. Int. J. Cardiol. 168, 692\u2013706 (2013).","journal-title":"Int. J. Cardiol."},{"key":"BFncomms15494_CR44","doi-asserted-by":"crossref","first-page":"4219","DOI":"10.4049\/jimmunol.153.9.4219","volume":"153","author":"PJ Mansfield","year":"1994","unstructured":"Mansfield, P. J. & Suchard, S. J. Thrombospondin promotes chemotaxis and haptotaxis of human peripheral blood monocytes. J. Immunol. 153, 4219\u20134229 (1994).","journal-title":"J. Immunol."},{"key":"BFncomms15494_CR45","first-page":"253","volume":"44","author":"MJ Goumans","year":"2000","unstructured":"Goumans, M. J. & Mummery, C. Functional analysis of the TGF beta receptor\/Smad pathway through gene ablation in mice. Int. J. Dev. Biol. 44, 253\u2013265 (2000).","journal-title":"Int. J. Dev. Biol."},{"key":"BFncomms15494_CR46","doi-asserted-by":"publisher","first-page":"26069","DOI":"10.1074\/jbc.M605040200","volume":"281","author":"JS Isenberg","year":"2006","unstructured":"Isenberg, J. S. et al. CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1. J. Biol. Chem. 281, 26069\u201326080 (2006).","journal-title":"J. Biol. Chem."},{"key":"BFncomms15494_CR47","doi-asserted-by":"publisher","first-page":"483","DOI":"10.4103\/2045-8932.105037","volume":"2","author":"DE Green","year":"2012","unstructured":"Green, D. E., Kang, B.-Y., Murphy, T. C. & Hart, C. M. Peroxisome proliferator-activated receptor gamma (PPAR\u03b3) regulates thrombospondin-1 and Nox4 expression in hypoxia-induced human pulmonary artery smooth muscle cell proliferation. Pulm. Circ. 2, 483\u2013491 (2012).","journal-title":"Pulm. Circ."},{"key":"BFncomms15494_CR48","doi-asserted-by":"publisher","first-page":"30778","DOI":"10.1074\/jbc.M205213200","volume":"277","author":"A-S Marsin","year":"2002","unstructured":"Marsin, A.-S., Bouzin, C., Bertrand, L. & Hue, L. The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J. Biol. Chem. 277, 30778\u201330783 (2002).","journal-title":"J. Biol. Chem."},{"key":"BFncomms15494_CR49","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.immuni.2015.02.001","volume":"42","author":"IN Shalova","year":"2015","unstructured":"Shalova, I. N. et al. Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1\u03b1. Immunity 42, 484\u2013498 (2015).","journal-title":"Immunity"},{"key":"BFncomms15494_CR50","doi-asserted-by":"publisher","first-page":"e1004372","DOI":"10.1371\/journal.ppat.1004372","volume":"10","author":"KM Vannella","year":"2014","unstructured":"Vannella, K. M. et al. Incomplete deletion of IL-4R\u03b1 by LysM(Cre) reveals distinct subsets of M2 macrophages controlling inflammation and fibrosis in chronic schistosomiasis. PLoS Pathog. 10, e1004372 (2014).","journal-title":"PLoS Pathog."},{"key":"BFncomms15494_CR51","doi-asserted-by":"publisher","first-page":"1562","DOI":"10.1002\/hep.24800","volume":"55","author":"H Hayashi","year":"2012","unstructured":"Hayashi, H., Sakai, K., Baba, H. & Sakai, T. Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in mice. Hepatology 55, 1562\u20131573 (2012).","journal-title":"Hepatology"},{"key":"BFncomms15494_CR52","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.cellimm.2014.07.007","volume":"291","author":"G Lauvau","year":"2014","unstructured":"Lauvau, G., Chorro, L., Spaulding, E. & Soudja, S. M. Inflammatory monocyte effector mechanisms. Cell Immunol. 291, 32\u201340 (2014).","journal-title":"Cell Immunol."},{"key":"BFncomms15494_CR53","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/nri3070","volume":"11","author":"C Shi","year":"2011","unstructured":"Shi, C. & Pamer, E. G. Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11, 762\u2013774 (2011).","journal-title":"Nat. Rev. Immunol."},{"key":"BFncomms15494_CR54","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.mam.2006.08.005","volume":"27","author":"E-L Eskelinen","year":"2006","unstructured":"Eskelinen, E.-L. Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol. Aspects Med. 27, 495\u2013502 (2006).","journal-title":"Mol. Aspects Med."},{"key":"BFncomms15494_CR55","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/mi.2015.34","volume":"9","author":"LA Borthwick","year":"2015","unstructured":"Borthwick, L. A. et al. Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis. Mucosal Immunol. 9, 38\u201355 (2015).","journal-title":"Mucosal Immunol."},{"key":"BFncomms15494_CR56","doi-asserted-by":"publisher","first-page":"89","DOI":"10.3389\/fimmu.2013.00089","volume":"4","author":"E Hams","year":"2013","unstructured":"Hams, E., Aviello, G. & Fallon, P. G. The schistosoma granuloma: friend or foe? Front. Immunol. 4, 89 (2013).","journal-title":"Front. Immunol."},{"key":"BFncomms15494_CR57","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1086\/674754","volume":"3","author":"NM Rogers","year":"2013","unstructured":"Rogers, N. M. et al. Cellular, pharmacological, and biophysical evaluation of explanted lungs from a patient with sickle cell disease and severe pulmonary arterial hypertension. Pulm. Circ. 3, 936\u2013951 (2013).","journal-title":"Pulm. Circ."},{"key":"BFncomms15494_CR58","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1186\/1471-2334-14-282","volume":"14","author":"RC Ferreira","year":"2014","unstructured":"Ferreira, R. C. et al. TGF beta and IL13 in schistosomiasis mansoni associated pulmonary arterial hypertension; a descriptive study with comparative groups. BMC Infect. Dis. 14, 282 (2014).","journal-title":"BMC Infect. Dis."},{"key":"BFncomms15494_CR59","first-page":"296","volume":"110","author":"AP Bandeira","year":"2004","unstructured":"Bandeira, A. P., Mendes, A. A., Santos-Filho, P., Sa, D. T. & Loureiro, R. Clinical efficacy of oral sildenafil in severe pulmonary hypertension in patients with chronic pulmonary schistosomiasis. Circulation 110, 296 (2004).","journal-title":"Circulation"},{"key":"BFncomms15494_CR60","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1378\/chest.11-0483","volume":"141","author":"CJ Fernandes","year":"2012","unstructured":"Fernandes, C. J. et al. The role of target therapies in schistosomiasis-associated pulmonary arterial hypertension. Chest 141, 923\u2013928 (2012).","journal-title":"Chest"},{"key":"BFncomms15494_CR61","doi-asserted-by":"publisher","first-page":"456","DOI":"10.4103\/2045-8932.93544","volume":"1","author":"BB Graham","year":"2011","unstructured":"Graham, B. B. et al. Significant intrapulmonary Schistosoma egg antigens are not present in schistosomiasis-associated pulmonary hypertension. Pulm. Circ. 1, 456\u2013461 (2011).","journal-title":"Pulm. Circ."},{"key":"BFncomms15494_CR62","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1164\/rccm.201101-0146OC","volume":"184","author":"A Crosby","year":"2011","unstructured":"Crosby, A. et al. Praziquantel reverses pulmonary hypertension and vascular remodeling in murine schistosomiasis. Am. J. Respir. Crit. Care Med. 184, 467\u2013473 (2011).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"BFncomms15494_CR63","doi-asserted-by":"publisher","first-page":"2711","DOI":"10.4049\/jimmunol.1100479","volume":"187","author":"M Li","year":"2011","unstructured":"Li, M. et al. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J. Immunol. 187, 2711\u20132722 (2011).","journal-title":"J. Immunol."},{"key":"BFncomms15494_CR64","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1093\/cvr\/cvn014","volume":"78","author":"M Das","year":"2008","unstructured":"Das, M., Burns, N., Wilson, S. J., Zawada, W. M. & Stenmark, K. R. Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKCzeta in the pulmonary artery adventitia. Cardiovasc. Res. 78, 440\u2013448 (2008).","journal-title":"Cardiovasc. Res."},{"key":"BFncomms15494_CR65","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.cvfa.2007.08.001","volume":"23","author":"TN Holt","year":"2007","unstructured":"Holt, T. N. & Callan, R. J. Pulmonary arterial pressure testing for high mountain disease in cattle. Vet. Clin. North Am. Food Anim. Pract. 23, 575\u2013596 vii (2007).","journal-title":"Vet. Clin. North Am. Food Anim. Pract."},{"key":"BFncomms15494_CR66","first-page":"11","volume":"48","author":"R Duran-Struuck","year":"2009","unstructured":"Duran-Struuck, R. & Dysko, R. C. Principles of bone marrow transplantation (BMT): providing optimal veterinary and husbandry care to irradiated mice in BMT studies. J. Am. Assoc. Lab. Anim. Sci. JAALAS 48, 11\u201322 (2009).","journal-title":"J. Am. Assoc. Lab. Anim. Sci. JAALAS"},{"key":"BFncomms15494_CR67","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1165\/rcmb.2012-0532OC","volume":"49","author":"BB Graham","year":"2013","unstructured":"Graham, B. B. et al. Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension. Am. J. Respir. Cell Mol. Biol. 49, 951\u2013959 (2013).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"BFncomms15494_CR68","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1046\/j.1365-2818.1997.2070765.x","volume":"186","author":"T Tandrup","year":"1997","unstructured":"Tandrup, T., Gundersen, H. J. & Jensen, E. B. The optical rotator. J. Microsc. 186, 108\u2013120 (1997).","journal-title":"J. Microsc."},{"key":"BFncomms15494_CR69","first-page":"328","volume":"39","author":"AW Cheever","year":"1968","unstructured":"Cheever, A. W. Conditions affecting the accuracy of potassium hydroxide digestion techniques for counting Schistosoma mansoni eggs in tissues. Bull. World Health Organ. 39, 328\u2013331 (1968).","journal-title":"Bull. World Health Organ."},{"key":"BFncomms15494_CR70","doi-asserted-by":"crossref","unstructured":"Howard, C. V. & Reed, M. G. Unbiased Stereology: Three-Dimensional Measurement in Microscopy BIOS Scientific Publ (2005).","DOI":"10.4324\/9780203006399"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms15494.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms15494","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/ncomms15494","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms15494.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T20:15:16Z","timestamp":1692821716000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms15494"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,30]]},"references-count":70,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,8,14]]}},"alternative-id":["BFncomms15494"],"URL":"https:\/\/doi.org\/10.1038\/ncomms15494","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,30]]},"assertion":[{"value":"13 June 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 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":"15494"}}