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From the Departments of Surgery,*
Cardiovascular
Surgery,
and
Cardiology,
Children’s Hospital, Boston; and
the Department of Pathology,
Brigham and
Women’s Hospital, Boston, Massachusetts
Cardiac valves arise from endocardial cushions, specialized
regions of the developing heart that are formed by an
endothelial-to-mesenchymal cell transdifferentiation. Whether and to
what extent this transdifferentiation is retained in mature heart
valves is unknown. Herein we show that endothelial cells from mature
valves can transdifferentiate to a mesenchymal phenotype. Using
induction of 
-smooth muscle actin (-SMA), an established
marker for this process, two distinct pathways of
transdifferentiation were identified in clonally derived endothelial
cell populations isolated from ovine aortic valve leaflets. -SMA
expression was induced by culturing clonal endothelial cells in medium
containing either transforming growth factor-ß or low levels of serum
and no basic fibroblast growth factor. Cells induced to express -SMA
exhibited markedly increased migration in response to platelet-derived
growth factor-BB, consistent with a mesenchymal phenotype. A
population of the differentiated cells co-expressed CD31, an
endothelial marker, along with -SMA, as seen by
double-label immunofluorescence. Similarly, this co-expression
of endothelial markers and -SMA was detected in a subpopulation of
cells in frozen sections of aortic valves, suggesting the
transdifferentiation may occur in vivo. Hence,
the clonal populations of valvular endothelial cells described here
provide a powerful in vitro model for dissecting
molecular events that regulate valvular endothelium.
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