| First Author | Kumar R | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Pages | 15494 | PubMed ID | 28555642 |
| Mgi Jnum | J:251682 | Mgi Id | MGI:5921192 |
| Doi | 10.1038/ncomms15494 | Citation | Kumar R, et al. (2017) TGF-beta activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension. Nat Commun 8:15494 |
| abstractText | 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-beta blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-beta 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. |
