Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification.
BACKGROUND
The bone morphogenetic proteins (BMPs), a family of morphogens, have been implicated as mediators of calcification and inflammation in the vascular wall.


OBJECTIVE
To investigate the effect of altered expression of matrix Gla protein (MGP), an inhibitor of BMP, on vascular disease.


RESULTS
We used MGP transgenic or MGP-deficient mice bred to apolipoprotein E mice, a model of atherosclerosis. MGP overexpression reduced vascular BMP activity, atherosclerotic lesion size, intimal and medial calcification, and inflammation. It also reduced expression of the activin-like kinase receptor 1 and the vascular endothelial growth factor, part of a BMP-activated pathway that regulates angiogenesis and may enhance lesion formation and calcification. Conversely, MGP deficiency increased BMP activity, which may explain the diffuse calcification of vascular medial cells in MGP deficient aortas and the increase in expression of activin-like kinase receptor 1 and vascular endothelial growth factor. Unexpectedly, atherosclerotic lesion formation was decreased in MGP-deficient mice, which may be explained by a dramatic reduction in expression of endothelial adhesion molecules limiting monocyte infiltration of the artery wall.


CONCLUSIONS
Our results indicate that BMP signaling is a key regulator of vascular disease, requiring careful control to maintain normal vascular homeostasis.
Yao
Yucheng
Y
Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1679, USA.
Bennett
Brian J
BJ
Wang
Xuping
X
Rosenfeld
Michael E
ME
Giachelli
Cecilia
C
Lusis
Aldons J
AJ
Boström
Kristina I
KI
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control*; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002114:Calcinosis / Q000378:metabolism / Q000517:prevention & control*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014652:Vascular Diseases / Q000378:metabolism / Q000517:prevention & control*; D000097568:Matrix Gla Protein
D001057:Apolipoproteins E; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D000097568:Matrix Gla Protein