A Selective TGFβ Ligand Trap Attenuates Pulmonary Hypertension.

RATIONALE Transforming Growth Factor-β (TGFβ) ligands signal via type I and type II serine-threonine kinase receptors to regulate broad transcriptional programs. Excessive TGFβ-mediated signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH), based in part on the ability of broad inhibitors of TGFβ/Activin/GDF/Nodal receptors ALK4/5/7 to attenuate experimental pulmonary hypertension (PH). These broad inhibition strategies do not delineate the specific contribution of TGFβ vs. a multitude of other ligands, and their translation is limited by cardiovascular and systemic toxicity. OBJECTIVE We tested the impact of TGFBRII-Fc, a selective TGFβ1/3 ligand trap, in several experimental PH models. METHODS Signaling studies utilized cultured human pulmonary artery smooth muscle cells. PH was studied in monocrotaline-treated Sprague-Dawley rats, SUGEN/hypoxia-treated Sprague-Dawley rats and SUGEN/hypoxia-treated C57BL/6 mice. PH, cardiac function, vascular remodeling, and valve structure were assessed by ultrasound, invasive hemodynamic measurements, and histomorphometry. MEASUREMENTS AND MAIN RESULTS TGFBRII-Fc is an inhibitor of TGFβ1 and TGFβ3 but not TGFβ2 signaling. In vivo, treatment with TGFBRII-Fc attenuated Smad2 phosphorylation, normalized expression of Pai-1, and mitigated PH and pulmonary vascular remodeling in monocrotaline-treated rats, SUGEN/hypoxia-treated rats and SUGEN/hypoxia-treated mice. Administration of TGFBRII-Fc to monocrotaline-treated or SUGEN/hypoxia-treated rats with established PH improved right ventricular systolic pressures, right ventricular function, and survival. No cardiac structural or valvular abnormalities were observed following treatment with TGFBRII-Fc. CONCLUSIONS Our findings are consistent with a pathogenetic role of TGFβ1/3, demonstrating the efficacy and tolerability of selective TGFβ ligand blockade for improving hemodynamics, remodeling, and survival in multiple experimental PH models.