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Journal of Lipid Research, Vol. 50, 521-533, March 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

A novel role for activating transcription factor-2 in 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis^*

Tieqiang Zhao^2,*, Dong Wang^2,*, Sergey Y. Cheranov^*, Manjula Karpurapu^*, Koteswara R. Chava^*, Venkatesh Kundumani-Sridharan^*, Dianna A. Johnson, John S. Penn and Gadiparthi N. Rao^1,*

^* Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163
Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163
Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232
² T. Zhao and D. Wang contributed equally to this work.

^* This work was supported by a grant (EY014856) from the National Eye Institute/National Institutes of Health.

Published, JLR Papers in Press, October 10, 2008

¹ To whom correspondence should be addressed. e-mail: grao{at}physio1.utmem.edu

To investigate the mechanisms underlying 15(S)-HETE-induced angiogenesis, we have studied the role of the small GTPase, Rac1. We find that 15(S)-HETE activated Rac1 in human retinal microvascular endothelial cells (HRMVEC) in a time-dependent manner. Blockade of Rac1 by adenovirus-mediated expression of its dominant negative mutant suppressed HRMVEC migration as well as tube formation and Matrigel plug angiogenesis. 15(S)-HETE stimulated Src in HRMVEC in a time-dependent manner and blockade of its activation inhibited 15(S)-HETE-induced Rac1 stimulation in HRMVEC and the migration and tube formation of these cells as well as Matrigel plug angiogenesis. 15(S)-HETE stimulated JNK1 in Src-Rac1-dependent manner in HRMVEC and adenovirus-mediated expression of its dominant negative mutant suppressed the migration and tube formation of these cells and Matrigel plug angiogenesis. 15(S)-HETE activated ATF-2 in HRMVEC in Src-Rac1-JNK1-dependent manner and interference with its activation via adenovirus-mediated expression of its dominant negative mutant abrogated migration and tube formation of HRMVEC and Matrigel plug angiogenesis. In addition, 15(S)-HETE-induced MEK1 stimulation was found to be dependent on Src-Rac1 activation. Blockade of MEK1 activation inhibited 15(S)-HETE-induced JNK1 activity and ATF-2 phosphorylation. Together, these findings show that 15(S)-HETE activates ATF-2 via the Src-Rac1-MEK1-JNK1 signaling axis in HRMVEC leading to their angiogenic differentiation.

Supplementary key words eicosanoid • Rac1 • retinal neovascularization

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