The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway
Abstract 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 ar...
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Nature Portfolio
2025-04-01
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| Online Access: | https://doi.org/10.1038/s41598-025-97627-7 |
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| author | Youpeng Jin Fei Mao Xuehui Wang Jie Zhang Yanting Gao Youfei Fan |
| author_facet | Youpeng Jin Fei Mao Xuehui Wang Jie Zhang Yanting Gao Youfei Fan |
| author_sort | Youpeng Jin |
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| description | Abstract 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. |
| format | Article |
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| language | English |
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| spelling | doaj-art-c0b8768930b840e79ca13f57fcb231312025-08-20T03:10:17ZengNature PortfolioScientific Reports2045-23222025-04-0115111410.1038/s41598-025-97627-7The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathwayYoupeng Jin0Fei Mao1Xuehui Wang2Jie Zhang3Yanting Gao4Youfei Fan5Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityAbstract 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.https://doi.org/10.1038/s41598-025-97627-7CyclopamineSonic hedgehogPulmonary arterial hypertensionBone morphogenetic protein receptor 2Pulmonary arterial remolding |
| spellingShingle | Youpeng Jin Fei Mao Xuehui Wang Jie Zhang Yanting Gao Youfei Fan The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway Scientific Reports Cyclopamine Sonic hedgehog Pulmonary arterial hypertension Bone morphogenetic protein receptor 2 Pulmonary arterial remolding |
| title | The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway |
| title_full | The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway |
| title_fullStr | The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway |
| title_full_unstemmed | The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway |
| title_short | The sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway |
| title_sort | sonic hedgehog signaling inhibitor cyclopamine improves pulmonary arterial hypertension via regulating the bone morphogenetic protein receptor 2 pathway |
| topic | Cyclopamine Sonic hedgehog Pulmonary arterial hypertension Bone morphogenetic protein receptor 2 Pulmonary arterial remolding |
| url | https://doi.org/10.1038/s41598-025-97627-7 |
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