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Wound Repair by Activated Heart Valve Interstitial Cells is Regulated by Transforming Growth Factor‐β

Valve interstitial cells (VICs) undergo phenotypic changes in response to valve injury and disease, expressing α‐smooth muscle actin (α‐SMA), a marker of activation. We tested the hypothesis that TGF‐β is an important regulator of VIC activation and repair. We created in vitro experimental wounds by mechanical denudation of a confluent monolayer cultured in M199 containing 10% fetal bovine serum 2% penicillin/streptomycin/amphotericin. In TGF‐β neutralizing antibody non‐treated and treated wounds, we characterized VIC activation, TGF‐β expression and apoptosis by α‐SMA, TGF‐β, activated caspase‐3 and annexin V immunofluorescence respectively. We also quantified proliferation by BrdU labeling and repair by measuring wound closure. VICs at the wound edge are activated showing prominent α‐SMA staining which decreases over 24–96 hours post‐wounding. Upon wound closure, α‐SMA staining becomes similar to that of a quiescent nonwounded monolayer. TGF‐β and pSmad2/3 staining are more prominent and apoptosis is observed more frequently at the wound edge at 24 hours post‐wounding compared to the nonwounded monolayer. Addition of TGF‐β neutralizing antibody decreases VIC activation, proliferation and wound closure in a dose‐dependent manner. In conclusion, wounding activates VICs which upregulate TGF‐β. TGF‐β maintains VIC activation and in turn regulates proliferation and wound repair.