Calcific nodule morphogenesis by heart valve interstitial cells is strain dependent

Area of Science:

• Cardiovascular Biology
• Biomedical Engineering
• Cellular Mechanobiology

Background:

• Calcific aortic valve disease (CAVD) impairs valve function, but its causes remain unknown.
• Aortic stiffening increases mechanical strain on aortic valves, a condition associated with CAVD.
• Transforming growth factor β1 (TGF-β1) and mechanical strain synergistically influence aortic valve interstitial cell (AVIC) phenotypes.

Purpose of the Study:

• To investigate the combined effects of mechanical strain and TGF-β1 on AVIC calcification.
• To elucidate the mechanisms by which strain and TGF-β1 induce AVIC calcification and nodule formation.

Main Methods:

• AVICs were pretreated with TGF-β1 and subjected to mechanical strain.
• Wound assays were used to assess cell tension and α-smooth muscle actin (αSMA) expression.
• A modified Lamé solution was used to analyze strain magnification in the cellular environment.

Main Results:

• TGF-β1 pretreatment followed by strain induced AVIC aggregation and calcification.
• Strain accelerated the calcification of aggregates into mature nodules with necrotic cores and apoptotic rings.
• Strain was found to inhibit AVIC migration and remodel cell contacts, impacting nodule formation.
• Strain magnification was identified as a key feature in the mechanical environment of nodule formation.

Conclusions:

• Mechanical strain, particularly when combined with TGF-β1, plays a critical role in AVIC calcification and nodule formation.
• Strain influences multiple stages of calcification, including cell tension, migration, apoptosis, and mineralization.
• Understanding strain-induced nodule formation offers novel therapeutic strategies for treating CAVD.