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Division of Cardiovascular Research, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
Our work has focused on the discovery that an
endogenous vascular elastase (EVE) plays a pivotal role in the vascular
changes associated with the development and progression of pulmonary
hypertension. Recent studies have identified serum factors that
stimulate transcription of this enzyme and have elucidated a signal
transduction process involving activation of the mitogen-activated
protein kinase pathway and nuclear expression of the transcription
factor AML1. Proteases release and activate growth factors that are
bound to the extracellular matrix and also induce, in a
3-integrin-dependent manner,
the transcription of the gene for the matrix glycoprotein tenascin. Tenascin alters smooth muscle cell shape and facilitates the
proliferative response to growth factors by clustering and activating
growth factor receptors. In addition, breakdown products of elastin, elastin peptides, can upregulate the production of fibronectin, a
glycoprotein that is critical to smooth muscle cell migration. The
mechanisms regulating enhanced fibronectin production have recently
been successfully targeted to prevent the development of intimal lesions.
endogenous vascular elastase; pulmonary hypertension; extracellular matrix; elastase; tenascin; fibronectin
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