Poster abstracts

Poster number 53 submitted by Matt VandeKopple

Mechanisms that promote activation of quiescent post natal valve interstitial cells

Matthew VandeKopple (Center for Cardiovascular and Pulmonary Research, Nationwide Childrens Hospital), Dr. Joy Lincoln (Center for Cardiovascular and Pulmonary Research, Nationwide Childrens Hospital)

Abstract:
Opening and closing of heart valve leaflets is largely achieved by the tri-laminar
organization of extracellular matrix (ECM) components including collagens,
proteoglycans and elastins that together, provide all the necessary biomechanical
properties for function throughout life. In contrast, disruption in ECM organization is a
histological landmark of valve disease. In healthy valves, the ECM is maintained by
valve interstitial cells (VICs) that are quiescent and fibroblast-like in the absence of
disease. However in response to pathological stimuli, quiescent VICs (qVICs) are
activated to a myofibroblast-like phenotype indicated by α-smooth muscle actin (α-SMA)
expression and organized stress fibers. In an activated state, VICs breakdown the healthy
ECM structure and replace it with alternative ECM components. These abnormal changes
alter the biomechanics of the valve and lead to dysfunction. Despite these observations,
the mechanisms that regulate VIC activation in post natal valves are unknown. Using
porcine and rat VIC systems, we show that VIC plasticity is dependent on substrate
stiffness and activation can be reversed by culturing on soft substrates. In addition, we
found that the bHLH transcription factor Scleraxis (Scx) is sufficient to promote VIC
activation in vitro and expression is increased with α-SMA in mouse models of valve
disease. Together these studies suggest that the extrinsic and intrinsic factors contribute
to VIC plasticity. Ongoing studies are currently examining the molecular and cellular
processes that drive activation of otherwise qVICs with the goal of providing insights for
the development of new mechanistic-based therapies in the prevention and treatment of
valve disease.

Keywords: Valve Interstitial Cells, Substrate Stiffness, Scleraxis