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 and Brian B. Graham ()
Additional contact information
Rahul Kumar: Program in Translational Lung Research, Anschutz Medical Campus
Claudia Mickael: Program in Translational Lung Research, Anschutz Medical Campus
Biruk Kassa: Program in Translational Lung Research, Anschutz Medical Campus
Liya Gebreab: Program in Translational Lung Research, Anschutz Medical Campus
Jeffrey C. Robinson: Program in Translational Lung Research, Anschutz Medical Campus
Daniel E. Koyanagi: Program in Translational Lung Research, Anschutz Medical Campus
Linda Sanders: Program in Translational Lung Research, Anschutz Medical Campus
Lea Barthel: National Jewish Health
Christina Meadows: Anschutz Medical Campus
Daniel Fox: Anschutz Medical Campus
David Irwin: Cardiovascular Pulmonary Research Laboratory, Anschutz Medical Campus
Min Li: Cardiovascular Pulmonary Research Laboratory, Anschutz Medical Campus
B. Alexandre McKeon: Cardiovascular Pulmonary Research Laboratory, Anschutz Medical Campus
Suzette Riddle: Cardiovascular Pulmonary Research Laboratory, Anschutz Medical Campus
R. Dale Brown: Cardiovascular Pulmonary Research Laboratory, Anschutz Medical Campus
Leslie E. Morgan: Anschutz Medical Campus
Christopher M. Evans: Anschutz Medical Campus
Daniel Hernandez-Saavedra: Program in Translational Lung Research, Anschutz Medical Campus
Angela Bandeira: Memorial S. Jose Hospital, Universidade de Pernambuco
James P. Maloney: Anschutz Medical Campus
Todd M. Bull: Anschutz Medical Campus
William J. Janssen: National Jewish Health
Kurt R. Stenmark: Cardiovascular Pulmonary Research Laboratory, Anschutz Medical Campus
Rubin M. Tuder: Program in Translational Lung Research, Anschutz Medical Campus
Brian B. Graham: Program in Translational Lung Research, Anschutz Medical Campus

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15494

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