5 research outputs found
Wnt signaling contributes to vascular calcification by induction of matrix metalloproteinases
Background Vascular calcifications such as arteriosclerosis, which is
characterized by a calcificiation of the tunica media, represent major
comorbidities e.g. in patients with chronic kidney disease (CKD). An essential
step during the development of arteriosclerosis is the
transdifferentiation/calcification of vascular smooth muscle cells (VSMC)
resembling osteogenesis. The matrix metalloproteinases (MMP)-2 and −9 were
shown to promote these VSMC calcifications and their inhibition is of
therapeutic value to prevent arteriosclerosis in preclinical studies. Aiming
for an understanding of the underlying regulatory mechanisms of MMPs we here
investigated, if the MMP-mediated VSMC calcification involves altered
signaling of the Wnt pathway, which is known to impact osteogenesis. Methods
We used an experimental in vitro model of vascular calcification.
Transdifferentiation/calcification of murine VSMC was induced by elevated
calcium and phosphorus levels. Calcification was assessed by calcium and
alkaline phosphatase measurements. Activation/activity of the gelatinases
MMP-2 and MMP-9 was assessed by conversion of fluorescence-labelled
substrates. Activation of the Wnt pathway was analysed by a reporter gene
assay. Results Besides pro-calcifying culture conditions, also activation of
Wnt signaling by a specific agonist (under normal culture conditions)
stimulated VSMC-calcification accompanied by enhanced expression and secretion
of the gelatinases MMP-2 and −9. Vice versa, recombinant MMP-2 and −9 induced
a time-delayed activation of Wnt signaling after 72 h in VSMC but showed no
direct effects after 24–48 h. These effects were blocked by pharmacological
inhibition of MMPs or of Wnt signaling. Conclusions Our study suggests that
the pro-calcifying environment in CKD induces Wnt signaling in VSMC which in
turn contributes to the induction of MMPs which then foster the development of
arteriosclerosis. Thus, besides MMP inhibition, the inhibition of Wnt
signaling in VSMC might represent a therapeutic target for the prevention of
vascular calcifications
Additional file 1: Figure S1. of Wnt signaling contributes to vascular calcification by induction of matrix metalloproteinases
It shows that direct effects of the MMP inhibitors on Wnt signaling in VSMC could be excluded. Figure S2. It shows that direct effects of the Wnt inhibitor on the enzymatic activities of the gelatinases MMP-2 and MMP-9 in VSMC could be excluded. (TIF 186 kb