Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 110, Issue 4, Pages 935-947Publisher
WILEY
DOI: 10.1002/jcb.22607
Keywords
CALCIFICATION; LINEAGE REPROGRAMMING; MYOCARDIN; Runx2/Cbfa1; SMOOTH MUSCLE CELLS
Categories
Funding
- NIH [R01 HL081785, HL62329, K01 DK075665, HL07828-06]
Ask authors/readers for more resources
Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. Smooth muscle cells (SMCs) may play an important role in vascular cartilaginous metaplasia and calcification via reprogramming to the osteochondrogenic state. To study whether SM lineage reprogramming and thus matrix calcification is reversible and what the necessary regulatory factors are to reverse this process, we used cells isolated from calcifying arterial medias of 4-week-old matrix Gla protein knockout mice (MGP-/-SMCs). We found that vascular cells with an osteochondrogenic phenotype regained SMC properties (positive for SM22 alpha and SM alpha-actin) and down-regulated osteochondrogenic gene expression (Runx2/Cbfa1 and osteopontin) upon culture in medium that favors SMC differentiation. Over time, the MGP-/-SMCs no longer expressed osteochondrogenic proteins and became indistinguishable from wild-type SMCs. Moreover, phenotypic switch of the restored SMCs to the osteochondrogenic state was re-induced by the pro-calcific factor, inorganic phosphate. Finally, loss- and gain-of-function studies of myocardin, a SM-specific transcription co-activator, and Runx2/Cbfa1, an osteochondrogenic transcription factor, revealed that upregulation of Runx2/Cbfa1, hut not loss of myocardin, played a critical role in phosphate-induced SMC lineage reprogramming and calcification. These results are the first to demonstrate reversibility of vascular SMCs in the osteochondrogenic state in response to local environmental cues, and that myocardin-enforced SMC lineage allocation was not sufficient to block vascular calcification. On the other hand, Runx2/Cbfa1 was found to be a decisive factor identified in the process. J. Cell. Biochem. 110: 935-947, 2010. (C) 2010 Wiley-Liss, Inc.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available