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

Pulmonary arterial hypertension ( PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-beta signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-b blockade can prevent experimental pulmonary hypertension ( PH) in pre-clinical models. TGF-b is regulated at the level of activation, but how TGF-beta is activated in this disease is unknown. Here we show TGF-beta 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-beta 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-beta could thus be a therapeutic approach in TGF-beta-dependent vascular diseases.