doi: 10.1161/CIRCULATIONAHA.107.726307
(Circulation. 2007;116:1221-1223.)
© 2007 American Heart Association, Inc.
Editorial |
Endothelium-Derived Bone Morphogenic Protein Antagonists May Counteract the Proatherogenic Vascular Effects of Bone Morphogenic Protein 4
From the Department of Physiology, New York Medical College, Valhalla.
Correspondence to Zoltan Ungvari, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail zoltan_ungvari{at}nymc.edu
Key Words: Editorials • atherosclerosis • endothelium • inflammation • shear stress
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Introduction |
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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-ß 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
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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-
B,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.
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Hemodynamic Forces Regulate Vascular Expression of BMP2/4 and BMP Antagonists |
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Our understanding of the factors that regulate vascular BMP2/4 expression also suggests a proatherogenic pathophysiological role for BMPs. It has been established that vascular inflammation and atherosclerosis develop in hemodynamically well-defined regions. During normal vascular homeostasis, laminar shear stress maintains an antiinflammatory, antiatherogenic phenotype of endothelial cells. In contrast, adverse changes in the hemodynamic environment, particularly a combination of low shear stress and increased wall tension (eg, resulting from high pressure), elicit proinflammatory phenotypic changes favoring atherogenesis. It is significant that expression of BMP2/4 is regulated by hemodynamic forces (Figure, C). In a series of elegant studies, Jo’s laboratory has demonstrated that expression of BMP4 in cultured endothelial cells is suppressed by initiation of laminar flow.1,5,6,13 We have recently shown that laminar shear stress regulates BMP4 (but not BMP2) expression both in cultured arteries in vitro and in animal models of increased shear stress in vivo.2 The transcriptional mechanisms by which shear stress regulates BMP4 expression are not completely understood and may include the cAMP/PKA pathway2 and mitogen-activated protein kinase signaling.18,19 In contrast to atheroprotective laminar shear stress, proatherogenic oscillatory shear stress upregulates BMP4 in endothelial cells.5,6,13 Previous studies have demonstrated that autocrine effects of BMP4 are responsible for the increased adhesiveness of activated monocytes to endothelial cells exposed to oscillatory shear stress.5,6 Expression of BMP2 is unaltered by shear stress2 but can be upregulated by cellular stretch in arteries exposed to high pressure.4 In coronary arterial endothelial cells, expression of BMP2 also is upregulated by proinflammatory stimuli such as tumor necrosis factor-
.3,4 Surprisingly, BMP4 does not seem to be readily induced by these stimuli.3 BMPs are produced from inactive precursors that are proteolytically cleaved. Then, the active ligand is secreted into the extracellular space. Binding of BMPs to their cognate receptors leads to phosphorylation of Smad proteins and activation of non–Smad-dependent intracellular signal-transducing pathways (eg, ERK1/2).3 Smad proteins form hetero-oligomers, translocate to the nucleus, and modulate transcription of target genes. Abundant data show that the BMP signal transduction cascade can be modulated at every step of this process: There are pseudoreceptors that compete with signaling receptors, inhibitory Smads, intracellular binding proteins that bind Smads, and factors that induce ubiquitination and proteolysis of Smads. In addition, a large number of BMP antagonists have emerged that function through direct association with specific BMPs, thus prohibiting BMPs from binding their cognate receptors. These BMP antagonists are secreted glycoproteins and include noggin, chordin, crossveinless-2, follistatin, matrix Gla protein, members of the Dan/Cerberus family, gremlin, and twisted gastrulation. The spatiotemporal regulation of BMP activity by BMP antagonists has been studied in the past mainly in developmental processes. The importance of the contribution from Chang et al1 is that it is one of the first studies to address the possible antiinflammatory regulatory role of BMP antagonists in endothelial cells.
It is clear from the study of Chang et al1 that the BMP antagonists follistatin, noggin, and matrix Gla protein are expressed in cultured endothelial cells. In setting out to prove that expression of BMP antagonists is regulated by shear stress, which they successfully did, the authors also turned up a number of unexpected observations. Contrary to their prediction, Chang et al1 report that oscillatory shear stress increased, whereas unidirectional laminar shear decreased, the expression of the BMP antagonists in endothelial cells. Of particular interest is that knockdown of the BMP antagonists noggin plus follistatin significantly increased monocyte adhesiveness to endothelial cells exposed to oscillatory shear stress. The results that treatment with recombinant follistatin and/noggin also decreased monocyte adhesion to a similar degree in both oscillatory shear–exposed and static cells are in complete agreement with this view. These findings suggest that coexpression of BMP4 and BMP antagonists may play a negative feedback role against the inflammatory response of BMP4 in atheroprone regions (Figure, C). The proposed model also predicts that the balance between BMP4 and BMP antagonists may change in pathophysiological conditions associated with an increased risk for atherosclerosis, favoring more proinflammatory BMP4 actions. An unexpected observation from this study is that knockdown of the BMP antagonists significantly increases monocyte adhesiveness to static endothelial cells as well. This interesting finding should provide a basis for further research into the role of BMP antagonists at various levels of shear stress. In addition, the mechanosensitive signaling pathways, which regulate the expression of BMP antagonists, need to be elucidated. Do similar pathways regulate the expression of BMP4 and its antagonists? What is the role of reactive oxygen species in the proposed negative feedback loops? Further studies also are needed to elucidate the role of other hemodynamic forces in controlling the expression of BMP antagonists (eg, high intraluminal pressure, increased wall tension, and/or increased pulse pressure). Chang et al1 convincingly showed that the expression pattern of BMP antagonists in the mouse aorta is consistent with the in vitro findings: Only endothelial cells in the lesser curvature exposed to disturbed flow, but not those in the greater curvature and straight arterial regions exposed to undisturbed flow, showed coexpression of BMP4 and the BMP antagonists. It will be of great interest to determine whether these new findings apply to other vascular beds (eg, whether other parts of the vascular tree show different expression pattern for BMP antagonists). Studies using various in vivo models of altered shear stress (eg, arteriovenous fistula models20) also would provide additional information about the in vivo coordinated regulation of BMPs and BMP antagonists. It will be equally interesting to address whether, in addition to its proposed role in conduit arteries, mechanosensitive regulation of BMPs and BMP antagonists can play a role in microvascular remodeling. Chang et al1 reported that in human coronary arteries, endothelial expression of BMP antagonists (similar to that of BMP4) positively correlated with the severity of atherosclerosis. Although it is tempting to speculate that upregulation of BMP4 and BMP antagonists during plaque development is due to the disturbed flow conditions in the diseased vascular segments, one cannot exclude the possibility that other atherogenic factors (eg, inflammatory stimuli, altered arachidonic acid metabolism) may play a role in this phenomenon. Finally, studies like those of Chang et al1 are extremely important because they identify novel pathways that could be targeted to attenuate vascular inflammation during the early phases of atherogenesis.
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Acknowledgments |
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Sources of Funding
Dr Ungvari’s research is supported by grants HL077256 from the National Heart, Lung, and Blood Institute of the National Institutes of Health and 0430108N from the American Heart Association.
Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionHemodynamic Forces Regulate...References |
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1. Chang K, Weiss D, Suo J, Vega JD, Giddens D, Taylor WR, Jo H. Bone morphogenic protein antagonists are coexpressed with bone morphogenic protein 4 in endothelial cells exposed to unstable flow in vitro in mouse aortas and in human coronary arteries: role of bone morphogenic protein antagonists in inflammation and atherosclerosis. Circulation. 2007; 116: 1258–1266.
2. Csiszar A, Labinskyy N, Smith KE, Rivera A, Bakker ETP, Jo H, Gardner J, Orosz Z, Ungvari Z. Downregulation of BMP-4 expression in coronary arterial endothelial cells: role of shear stress and the cAMP/PKA pathway. Arterioscler Thromb Vasc Biol. 2007; 27: 776–782.
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5. Sorescu GP, Song H, Tressel SL, Hwang J, Dikalov S, Smith DA, Boyd NL, Platt MO, Lassegue B, Griendling KK, Jo H. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a Nox1-based NADPH oxidase. Circ Res. 2004; 95: 773–779.
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