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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:785.)
© 2001 American Heart Association, Inc.

Vascular Biology

Upregulatory Expression of Furin and Transforming Growth Factor-ß by Fluid Shear Stress in Vascular Endothelial Cells

Mitsuko Negishi; Danhong Lu; You-Qing Zhang; Yoshie Sawada; Toshiki Sasaki; Tsuyoshi Kayo; Joji Ando; Tetsuro Izumi; Masahiko Kurabayashi; Itaru Kojima; Hirotake Masuda; Toshiyuki Takeuchi

From the Departments of Molecular Medicine (M.N., D.L., Y.S., T.I., T.T.) and Cell Biology (Y.-Q.Z., I.K.), Institute for Molecular and Cellular Regulation, Gunma University, and the Second Department of Internal Medicine (M.N., M.K.), Gunma University School of Medicine, Maebashi, Japan; the Department of Biomedical Engineering (J.A.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and the Department of Pathology (T.S., T.K., H.M.), Akita University School of Medicine, Akita, Japan.

Correspondence to Toshiyuki Takeuchi, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Showa-machi, Maebashi 371-8512, Japan. E-mail tstake{at}showa.gunma-u.ac.jp

Abstract—Furin, a yeast Kex2-family endoprotease, converts many vasoregulatory propeptides, including pro-transforming growth factor (TGF)-ß to their mature forms. We examined whether furin expression is regulated by shear stress in vivo and in vitro. When an arteriovenous shunt was placed between the carotid artery and external jugular vein in rabbits, furin and TGF-ß were highly expressed in shear stress–loaded endothelial cells. Exposure of bovine aortic endothelial cells in culture to shear stress induced furin and TGF-ß expression in a similar manner. Molecular analysis of furin expression in bovine aortic endothelial cells revealed that shear stress increases the furin gene expression at transcriptional levels. Furthermore, TGF-ß itself increased the furin mRNA levels. Shear-mediated furin expression was partly mediated by TGF-ß because shear-induced furin mRNA levels were considerably decreased by overexpression of the truncated form of the TGF-ß type II receptor. Likewise, blockade of furin activity by a furin inhibitor significantly decreased the endothelial production of mature TGF-ß. Taken together, the results indicate that furin expression is induced and maintained by a coordination of shear stress and TGF-ß. Increased furin expression may facilitate the formation of mature TGF-ß, resulting in the enhanced effects of TGF-ß on endothelial cells and vascular smooth muscle cells in the vasculature.

Key Words: transforming growth factor-ß • furin • endoprotease • shear stress • endothelial cells

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