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 journalArticlepeer-review

80 Scopus citations


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 languageEnglish (US)
Article number15494
JournalNature communications
StatePublished - May 30 2017
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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