Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated...

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Biomedical Engineering

Background:

• Aortic valve disease affects over 2% of the population, leading to calcification and stenosis.
• Current treatments are limited to surgery due to poor understanding of disease mechanisms.
• Valve interstitial cells differentiate into bone-like cells, causing leaflet stiffening.

Purpose of the Study:

• Investigate mechanisms underlying pathological phenotypes in valve interstitial cells.
• Identify early indicators of calcific aortic valve disease.
• Explore novel therapeutic targets for aortic valve stenosis.

Main Methods:

• Utilized in vitro and in vivo models with mouse, porcine, and human tissues.
• Assessed Sox9 expression and nuclear localization in valve interstitial cells.
• Examined the role of valve endothelial cells and TGF-β1 in regulating Sox9 and calcification.

Main Results:

• Reduced Sox9 expression and nuclear localization precede aortic valve calcification.
• Valve endothelial cells inhibit Sox9 nuclear export and calcific nodule formation in vitro.
• Loss of endothelial TGF-β1 in vivo reduces Sox9 expression and promotes calcific aortic valve disease.

Conclusions:

• Decreased nuclear Sox9 in valve interstitial cells is an early marker for calcification.
• Pharmacological inhibition of Sox9 nuclear export presents a potential therapeutic strategy.
• This approach could prevent aortic valve calcification and stenosis progression.