Inhibition of Bone Morphogenetic Proteins Protects Against Atherosclerosis and Vascular Calcification

Abstract

Rationale: 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. Methods and 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.