Regulation of Bone Morphogenetic Protein-2 Expression in Endothelial Cells

Abstract

Background-Recent studies suggest that bone morphogenetic protein-2 (BMP-2), a transforming growth factor-␤ superfamily member cytokine, plays an important role both in vascular development and pathophysiological processes, including endothelial activation that is likely to contribute to the development of coronary atherosclerosis, yet the factors that regulate arterial expression of BMP-2 are completely unknown. We tested the hypothesis that BMP-2 expression in endothelial cells is governed by an H 2 O 2 and nuclear factor (NF)-〉-dependent pathway that can be activated by both proinflammatory and mechanical stimuli. Methods and Results-The proinflammatory cytokine tumor necrosis factor (TNF)-␣ induced NF-〉 activation and elicited significant increases in BMP-2 mRNA and protein in primary coronary arterial endothelial cells and human umbilical vein endothelial cells that were prevented by NF-〉 inhibitors (pyrrolidine dithiocarbamate and SN-50), silencing of p65 (siRNA), or catalase. Administration of H 2 O 2 also elicited NF-〉 activation and BMP-2 induction. In organ culture, exposure of rat arteries to high pressure (160 mm Hg) elicited H 2 O 2 production, nuclear translocation of NF-〉, and upregulation of BMP-2 expression. Although high pressure upregulated TNF-␣, it appears that it directly regulates BMP-2 expression, because upregulation of BMP-2 was also observed in vessels of TNF-␣ knockout mice. Key Words: free radicals Ⅲ cytokines Ⅲ growth factors T he transforming growth factor superfamily member cytokine, bone morphogenetic protein-2 (BMP-2), was originally detected in cartilage and bone 1 ; however, recent studies from this and other laboratories demonstrated that vascular endothelial and smooth muscle cells are also a significant source of BMPs. [2][3][4][5][6] First genetic analysis of patients with primary pulmonary hypertension indicated that a vascular BMP-2/BMP receptor system plays an important role in vascular physiology. 7,8 Indeed, BMP-2 has been shown to regulate a host of cellular functions, 2,4,5,9 including cardiovascular development, 9 neovascularization in tumors, 10 and smooth muscle cell chemotaxis in response to vascular injury. 2 Both BMP-2 (unpublished observation, 2004) and BMP-4, which are closely related by their amino acid sequence and act on the same receptor, 4,6 were shown to exert proinflammatory effects by inducing expression of adhesion molecules and enhancing monocyte adhesion. Endotheliumderived BMPs are also osteoinductive, 5 and hypotheses have been put forward that they may also contribute to vascular calcification during the development of atherosclerotic plaques. 3,5,11 Importantly, recent studies confirmed a striking upregulation of BMP-2/4 in atherosclerotic lesions. [2][3][4] Despite the growing evidence for the physiological/pathophysiological importance of BMP-2 in blood vessels, the mechanisms regulating endothelial BMP-2 expression have not yet been elucidated. Previously, we 12 have demonstrated that in coronary arteries in hyperhomocysteinemia, vascular i...

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