Asthma is a chronic respiratory disease characterized by reversible
airway obstruction with persistent airway
inflammation and
airway remodeling. Features of
airway remodeling include increased airway smooth muscle (ASM) mass. A
disintegrin and
metalloproteinase (ADAM)-33 has been identified as playing a role in the pathophysiology of
asthma. ADAM-33 is expressed in ASM cells and is suggested to play a role in the function of these cells. However, the regulation of ADAM-33 is not fully understood.
Vascular endothelial growth factor (
VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthmatics. Although
VEGF was initially thought of as an endothelial-specific
growth factor, recent reports have found that
VEGF can promote proliferation of other cell types, including ASM cells. To investigate the precise mechanism of
VEGF's effect on ASM cell proliferation, we tested the expression of ADAM-33, phospho-extracellularsignal-regulated
kinase 1/2 (ERK1/2), and phospho-Akt in
VEGF-stimulated ASM cells. We found that
VEGF up-regulates ADAM-33
mRNA and
protein levels in a dose- and time-dependent manner as well as phosphorylation of ERK1/2 and Akt. We also found that
VEGF-induced ASM cell proliferation is inhibited by both ADAM-33 knockdown and a selective
VEGF receptor 2 (VEGFR2) inhibitor (
SU1498). Furthermore,
VEGF-induced ADAM-33 expression and ASM cell proliferation were suppressed by inhibiting ERK1/2 activity, but not by inhibiting Akt activity. Collectively, our findings suggest that
VEGF enhances ADAM-33 expression and ASM cell proliferation by activating the VEGFR2/ERK1/2 signaling pathway, which might be involved in the pathogenesis of
airway remodeling. Further elucidation of the mechanisms underlying these observations might help develop therapeutic strategies for airway diseases associated with smooth muscle
hyperplasia such as
asthma.