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.
Highlights
Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries
Since we found evidence that bone marrow (BM)-derived Ly6C þ monocytes were the source of TSP-schistosomiasis-induced pulmonary hypertension (PH), we investigated the expression of chemokines that can recruit these cells to the lung perivascular compartment; we found higher messenger RNA (mRNA) levels of Ccl[2], Ccl[7] and Ccl[12] in sorted tissue or interstitial macrophages (Supplementary Fig. 15)
We observed TSP-1 blockade protected against transforming growth factor (TGF)-b-mediated pulmonary vascular disease, due to both Schistosoma and chronic hypoxia exposure (Fig. 7)
Summary
Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-b signalling with idiopathic, heritable and autoimmune-associated etiologies; TGF-b blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. Blockade of TGF-b is effective in multiple pre-clinical models of experimental pulmonary hypertension (PH), including experimental hypoxia, monocrotaline and exposure to the parasite Schistosoma mansoni[3,6,7]. Multiple proteins can activate TGF-b by removing the LAP, including the integrins avb[6] and avb[8], and the thrombospondins (TSPs)[10,11,12,13,14,15,16] It remains unclear how pathologic TGF-b is activated in PAH, in the perivascular space where it would have localized paracrine effects on the vascular cells. The potential role of TSP1 as the activator of TGF-b in PH and in particular PH caused by the parasite S. mansoni has not been addressed
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