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J. Biol. Chem., Vol. 278, Issue 33, 31128-31135, August 15, 2003

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Bone Morphogenic Protein 4 Produced in Endothelial Cells by Oscillatory Shear Stress Stimulates an Inflammatory Response^*

George P. Sorescu , Michelle Sykes , Daiana Weiss , Manu O. Platt , Aniket Saha , Jinah Hwang , Nolan Boyd , Yong C. Boo , J. David Vega ¶, W. Robert Taylor  and Hanjoong Jo   ||

From the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University and the Division of Cardiology and ^¶Department of Surgery, Emory University, Atlanta, Georgia 30322

Atherosclerosis is now viewed as an inflammatory disease occurring preferentially in arterial regions exposed to disturbed flow conditions, including oscillatory shear stress (OS), in branched arteries. In contrast, the arterial regions exposed to laminar shear (LS) are relatively lesion-free. The mechanisms underlying the opposite effects of OS and LS on the inflammatory and atherogenic processes are not clearly understood. Here, through DNA microarrays, protein expression, and functional studies, we identify bone morphogenic protein 4 (BMP4) as a mechanosensitive and pro-inflammatory gene product. Exposing endothelial cells to OS increased BMP4 protein expression, whereas LS decreased it. In addition, we found BMP4 expression only in the selective patches of endothelial cells overlying foam cell lesions in human coronary arteries. The same endothelial patches also expressed higher levels of intercellular cell adhesion molecule-1 (ICAM-1) protein compared with those of non-diseased areas. Functionally, we show that OS and BMP4 induced ICAM-1 expression and monocyte adhesion by a NFB-dependent mechanism. We suggest that BMP4 is a mechanosensitive, inflammatory factor playing a critical role in early steps of atherogenesis in the lesion-prone areas.

Received for publication, January 21, 2003 , and in revised form, May 22, 2003.

^* This work was supported by Grants HL71014, HL67413, and HL70531 from the National Institute of Health (to H. J. and W. R. T.), NASA (NAG2-1431), and the Whitaker Foundation (H. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Wallace H. Coulter Dept. of Biomedical Engineering at Georgia Tech and Emory University, Atlanta, GA 30322. Tel.: 404-712-9654; Fax: 404-727-3330; E-mail: hanjoong.jo{at}bme.gatech.edu.

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