Endothelium-Derived Bone Morphogenic Protein Antagonists May Counteract the Proatherogenic Vascular Effects of Bone Morphogenic Protein 4

Abstract

In the present issue of Circulation , Chang et al1 report novel shear stress–sensitive paracrine mechanisms that regulate the activity of bone morphogenetic proteins (BMPs) in the vascular wall. BMP2 and BMP4 are structurally related members of the transforming growth factor-β superfamily. Recent studies demonstrated that vascular endothelial and smooth muscle cells are a significant source of BMPs,2–8 which regulate a host of cellular functions, including cardiovascular development,9 neovascularization in tumors,10 and smooth muscle cell chemotaxis in response to vascular injury,11 and control the balance between proliferation and activation of apoptosis in pulmonary arterial endothelial and smooth muscle cells.12 Article p 1258 Many lines of evidence suggest that BMPs may function as proinflammatory, prohypertensive, and proatherogenic mediators in the vessel wall.13 Recent studies have demonstrated a striking upregulation of BMP2/4 in atheroprone vascular regions and atherosclerotic lesions,5,6,11,14,15 and hypotheses have been put forward that endothelium-derived BMPs contribute to vascular calcification (reviewed elsewhere16,17). In vitro, BMP2 and BMP4 were shown to exert proinflammatory effects. Activation of BMP signaling by either overexpression of BMP2/4 in vascular cells or administration of recombinant BMPs activates NAD(P)H oxidases, which results in cellular oxidative stress and endothelial dysfunction (Figure, A and B).13 Chronic BMP4 infusion in C57Bl/6 and apolipoprotein-null mice also impairs endothelium-dependent vasodilation and induces arterial hypertension in an NAD(P)H oxidase–dependent manner.8 BMP2 and BMP4 also elicit endothelial activation, thus enhancing monocyte adhesiveness.1,3–6 Evidence indicates that in endothelial cells BMP2 and BMP4 activate mitogen-activated protein kinase pathways and nuclear factor-κB,3,6 at least in part, via NAD(P)H oxidase–dependent pathways. Future studies will elucidate in detail the role of BMP receptor subtypes and the interaction between downstream signaling mechanisms induced by BMP2/4 that mediate their proinflammatory effects in the cardiovascular system. A, BMP4 …