TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension

Rahul Kumar; Claudia Mickael; Biruk Kassa; Liya Gebreab; Jeffrey C. Robinson; Daniel E. Koyanagi; Linda Sanders; Lea Barthel; Christina Meadows; Daniel Fox; David Irwin; Min Li; B. Alexandre McKeon; Suzette Riddle; R. Dale Brown; Leslie E. Morgan; Christopher M. Evans; Daniel Hernandez-Saavedra; Angela Bandeira; James P. Maloney; Todd M. Bull; William J. Janssen; Kurt R. Stenmark; Rubin M. Tuder; Brian B. Graham

doi:10.1038/ncomms15494

TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension

Rahul Kumar, Claudia Mickael, Biruk Kassa, Liya Gebreab, Jeffrey C. Robinson, Daniel E. Koyanagi, Linda Sanders, Lea Barthel, Christina Meadows, Daniel Fox, David Irwin, Min Li, B. Alexandre McKeon, Suzette Riddle, R. Dale Brown, Leslie E. Morgan, Christopher M. Evans, Daniel Hernandez-Saavedra, Angela Bandeira, James P. MaloneyTodd M. Bull, William J. Janssen, Kurt R. Stenmark, Rubin M. Tuder, Brian B. Graham

Research output: Contribution to journal › Article › peer-review

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Abstract

Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-β signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-β blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-β is regulated at the level of activation, but how TGF-β is activated in this disease is unknown. Here we show TGF-β activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-β 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-β could thus be a therapeutic approach in TGF-β-dependent vascular diseases.

Original language	English (US)
Article number	15494
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15494
State	Published - May 30 2017
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Kumar, R., Mickael, C., Kassa, B., Gebreab, L., Robinson, J. C., Koyanagi, D. E., Sanders, L., Barthel, L., Meadows, C., Fox, D., Irwin, D., Li, M., McKeon, B. A., Riddle, S., Brown, R. D., Morgan, L. E., Evans, C. M., Hernandez-Saavedra, D., Bandeira, A., ... Graham, B. B. (2017). TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension. Nature communications, 8, Article 15494. https://doi.org/10.1038/ncomms15494

Kumar, R, Mickael, C, Kassa, B, Gebreab, L, Robinson, JC, Koyanagi, DE, Sanders, L, Barthel, L, Meadows, C, Fox, D, Irwin, D, Li, M, McKeon, BA, Riddle, S, Brown, RD, Morgan, LE, Evans, CM, Hernandez-Saavedra, D, Bandeira, A, Maloney, JP, Bull, TM, Janssen, WJ, Stenmark, KR, Tuder, RM & Graham, BB 2017, 'TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension', Nature communications, vol. 8, 15494. https://doi.org/10.1038/ncomms15494

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title = "TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension",

abstract = "Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-β signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-β blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-β is regulated at the level of activation, but how TGF-β is activated in this disease is unknown. Here we show TGF-β activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-β 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-β could thus be a therapeutic approach in TGF-β-dependent vascular diseases.",

author = "Rahul Kumar and Claudia Mickael and Biruk Kassa and Liya Gebreab and Robinson, {Jeffrey C.} and Koyanagi, {Daniel E.} and Linda Sanders and Lea Barthel and Christina Meadows and Daniel Fox and David Irwin and Min Li and McKeon, {B. Alexandre} and Suzette Riddle and Brown, {R. Dale} and Morgan, {Leslie E.} and Evans, {Christopher M.} and Daniel Hernandez-Saavedra and Angela Bandeira and Maloney, {James P.} and Bull, {Todd M.} and Janssen, {William J.} and Stenmark, {Kurt R.} and Tuder, {Rubin M.} and Graham, {Brian B.}",

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doi = "10.1038/ncomms15494",

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T1 - TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension

AU - Kumar, Rahul

AU - Mickael, Claudia

AU - Kassa, Biruk

AU - Gebreab, Liya

AU - Robinson, Jeffrey C.

AU - Koyanagi, Daniel E.

AU - Sanders, Linda

AU - Barthel, Lea

AU - Meadows, Christina

AU - Fox, Daniel

AU - Irwin, David

AU - Li, Min

AU - McKeon, B. Alexandre

AU - Riddle, Suzette

AU - Brown, R. Dale

AU - Morgan, Leslie E.

AU - Evans, Christopher M.

AU - Hernandez-Saavedra, Daniel

AU - Bandeira, Angela

AU - Maloney, James P.

AU - Bull, Todd M.

AU - Janssen, William J.

AU - Stenmark, Kurt R.

AU - Tuder, Rubin M.

AU - Graham, Brian B.

PY - 2017/5/30

Y1 - 2017/5/30

N2 - Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-β signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-β blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-β is regulated at the level of activation, but how TGF-β is activated in this disease is unknown. Here we show TGF-β activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-β 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-β could thus be a therapeutic approach in TGF-β-dependent vascular diseases.

AB - Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-β signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-β blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-β is regulated at the level of activation, but how TGF-β is activated in this disease is unknown. Here we show TGF-β activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-β 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-β could thus be a therapeutic approach in TGF-β-dependent vascular diseases.

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TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension

Abstract

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