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J Biol Chem, Vol. 273, Issue 13, 7547-7553, March 27, 1998
cAMP Stimulates Osteoblast-like Differentiation of Calcifying
Vascular Cells
POTENTIAL SIGNALING PATHWAY FOR VASCULAR CALCIFICATION
Yin
Tintut,
Farhad
Parhami,
Kristina
Boström,
Simon M.
Jackson, and
Linda L.
Demer
From the Division of Cardiology, Departments of Medicine and
Physiology, UCLA School of Medicine,
Los Angeles, California 90095-1679
The role of the cAMP signaling pathway in
vascular calcification was investigated using calcifying vascular cells
(CVC) derived from primary aortic medial cell cultures. We previously
showed that CVC have fibroblastic morphology and express several
osteoblastic differentiation markers. After confluency, they aggregate
into cellular condensations, which later mature into nodules where mineralization is localized. Here, we investigated the effects of cAMP
on CVC differentiation because it plays a role in both osteoblastic
differentiation and vascular disease. Dibutyryl-cAMP or forskolin
treatment of CVC for 3 days induced osteoblast-like "cuboidal"
morphology, inhibited proliferation, and enhanced alkaline phosphatase
activity, all early markers of osteoblastic differentiation. Isobutylmethylxanthine and cholera toxin had the same effects. Treatment of CVC with pertussis toxin, however, did not induce the
morphological change or increase alkaline phosphatase activity, although it inhibited CVC proliferation to a similar extent. cAMP also
increased type I procollagen production and gene expression of matrix
-carboxyglutamic acid protein, recently shown to play a role in
in vivo vascular calcification. cAMP inhibited the
expression of osteopontin but did not affect the expression of
osteocalcin and core binding factor. Prolonged cAMP treatment enhanced
matrix calcium-mineral incorporation but inhibited the condensations resulting in diffuse mineralization throughout the monolayer of cells.
Treatment of CVC with a protein kinase A-specific inhibitor, KT5720,
inhibited alkaline phosphatase activity and mineralization during
spontaneous CVC differentiation. These results suggest that the cAMP
pathway promotes in vitro vascular calcification by
enhancing osteoblast-like differentiation of CVC.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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