In smokers, Sonic hedgehog modulates pulmonary endothelial function through vascular endothelial growth factor

Area of Science:

• Cardiovascular Biology
• Pulmonary Medicine
• Endothelial Function

Background:

• Tobacco use significantly contributes to pulmonary vascular disease, primarily through endothelial dysfunction.
• The Sonic hedgehog (SHH) signaling pathway plays a crucial role in maintaining vascular physiology.
• Understanding the SHH pathway's involvement in smoking-related endothelial dysfunction is vital for targeted therapeutic strategies.

Purpose of the Study:

• To investigate the role of the Sonic hedgehog (SHH) pathway in pulmonary endothelial dysfunction observed in smokers.
• To determine if SHH pathway modulation affects endothelium-dependent relaxation in pulmonary arteries of smokers.

Main Methods:

• Comparing ex vivo endothelium-dependent relaxation of pulmonary artery rings from smokers and never-smokers in response to acetylcholine (Ach).
• Assessing the impact of SHH pathway inhibitors (GANT61, cyclopamine) and an activator (SAG) on Ach-induced relaxation.
• Quantifying VEGF levels and SHH pathway gene expression in pulmonary artery rings using ELISA and RT-qPCR.

Main Results:

• Smokers exhibited significantly reduced Ach-induced relaxation compared to never-smokers (24% vs. 50%).
• SHH pathway genes were expressed in pulmonary artery rings from smokers; SHH inhibition impaired relaxation and VEGF expression.
• Recombinant VEGF restored endothelial function, and VEGF levels correlated with relaxation and smoking history (pack-years).

Conclusions:

• The Sonic hedgehog (SHH) pathway is active in the pulmonary arteries of smokers.
• SHH pathway components and their interaction with VEGF are critical in modulating endothelial function in the context of smoking.
• Targeting the SHH-VEGF axis may offer a novel therapeutic approach for tobacco-induced pulmonary vascular complications.