The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway.

Pulmonary arterial hypertension (PAH) is a severe and progressive disease with hallmarks of pulmonary vascular remodeling and bone morphogenetic protein receptor 2 (BMPR2) mutation. Recent studies indicate Sonic hedgehog (SHH) signaling is involved in the proliferation of human pulmonary arterial smooth muscle cells (hPASMCs) but the role of the SHH signaling inhibitor cyclopamine in monocrotaline (MCT)-induced PAH has not been investigated. We hypothesized SHH promotes pulmonary vascular remodeling and that inhibition of SHH signaling by cyclopamine could attenuate pulmonary hypertension via the bone morphogenetic protein (BMP) pathway. SHH and BMPR2 proteins were measured in pulmonary arteries isolated from MCT-induced PAH rats and in hPASMCs. The therapeutic effects of cyclopamine were tested in PAH rats and in BMPR2 knockdown hPASMCs. SHH protein levels were increased in PAH rats and exogenous recombinant SHH protein promoted proliferation of hPASMCs via BMPR2 and osteopontin. Furthermore, cyclopamine attenuated hemodynamics and vascular remodeling via the BMP pathway in PAH rats. Finally, cyclopamine enhanced apoptosis and reduced proliferation in hPASMCs with impaired BMPR2. The findings of this study provide evidence that SHH has a role in pulmonary vascular remodeling via BMP4/BMPR2/ID1, and its inhibition by cyclopamine could be a potential therapeutic target in PAH.