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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:594.)
© 2003 American Heart Association, Inc.

Vascular Biology

TWEAK Is an Endothelial Cell Growth and Chemotactic Factor That Also Potentiates FGF-2 and VEGF-A Mitogenic Activity

Patrick J. Donohue; Christine M. Richards; Sharron A.N. Brown; Heather N. Hanscom; John Buschman; Shobha Thangada; Timothy Hla; Mark S. Williams; Jeffrey A. Winkles

From the Departments of Vascular Biology (P.J.D., C.M.R., S.A.N.B., H.N.H., J.B., J.A.W.) and Immunology (M.S.W.), Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, Md; the Departments of Biochemistry and Molecular Biology (J.A.W.) and Immunology (M.S.W.) and the Institute for Biomedical Sciences (J.A.W., M.S.W.), George Washington University Medical Center, Washington, DC; and the Center for Vascular Biology (S.T., T.H.,), Department of Physiology, University of Connecticut Health Center, Farmington, Conn.

Correspondence to Jeffrey A. Winkles, Department of Vascular Biology, Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855. E-mail winkles{at}usa.redcross.org

Objective— TWEAK, a member of the tumor necrosis factor superfamily, binds to the Fn14 receptor and stimulates angiogenesis in vivo. In this study, we investigated Fn14 gene expression in human endothelial cells (ECs) and examined the effect of TWEAK, added either alone or in combination with fibroblast growth factor-2 (FGF-2) or vascular endothelial growth factor-A (VEGF-A), on EC proliferation, migration, and survival in vitro. We also determined whether a soluble Fn14-Fc fusion protein could inhibit TWEAK biologic activity on ECs and investigated TWEAK signal transduction in ECs.

Methods and Results— We found that both FGF-2 and VEGF-A could induce Fn14 mRNA expression in ECs. TWEAK was a mitogen for ECs, and this proliferative activity could be inhibited by an Fn14-Fc decoy receptor. Furthermore, TWEAK treatment activated several intracellular signaling pathways in ECs and potentiated FGF-2– and VEGF-A–stimulated EC proliferation. TWEAK also had EC chemotactic activity, but it did not promote EC survival.

Conclusions— These results indicate that TWEAK is an EC growth and migration factor but not a survival factor. TWEAK can also enhance both FGF-2 and VEGF-A mitogenic activity on ECs. Thus, TWEAK may act alone as well as in combination with FGF-2 or VEGF-A to regulate pathological angiogenesis.

Key Words: TWEAK • Fn14 • fibroblast growth factor • vascular endothelial growth factor • endothelial cells

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