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Abstract
During embryonic development, cells comprising the outermost layer of the heart or
epicardium play a critical role in the formation of the coronary vasculature. Thus,
uncovering the molecular mechanisms that govern epicardial cell behavior is imperative
to better understand the etiology of cardiovascular diseases. In this study, we investigated
the function of hyaluronan (HA), a major component of the extracellular matrix, in
the modulation of epicardial signaling. We show that stimulation of epicardial cells
with high molecular weight HA (HMW-HA) promotes the association of MEKK1 with the
HA receptor CD44 and induces MEKK1 phosphorylation. This leads to the activation of
two distinct pathways, one ERK-dependent and another NFkappaB-dependent. Furthermore,
HMW-HA stimulates epicardial cells to differentiate and invade, as suggested by increased
vimentin expression and enhanced invasion through a collagen matrix. Blockade of CD44,
transfection with a kinase-inactive MEKK1 construct or the use of ERK1/2 and NFkappaB
inhibitors significantly abrogates the invasive response to HMW-HA. Together, these
findings suggest an important role for HA in the regulation of epicardial cell fate
via activation of MEKK1 signaling cascades.
Published by Elsevier Inc.