Youpeng Jin, Fei Mao, Xuehui Wang, Jie Zhang, Yanting Gao, Youfei Fan
Shandong Provincial Hospital, First Affiliated Hospital and Shandong First Medical University.
China
Scientific Reports
Sci Rep 2025; 15:
DOI: 10.1038/s41598-025-97627-7
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.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Genetic Factors Associated with Pulmonary Vascular Disease
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes