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(Investigative Ophthalmology and Visual Science. 2007;48:4930-4938.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0617
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15(S)-HETE Production in Human Retinal Microvascular Endothelial Cells by Hypoxia: Novel Role for MEK1 in 15(S)-HETE–Induced Angiogenesis

Arun K. Bajpai,1 Eva Blaskova,1 Suresh B. Pakala,1 Tieqiang Zhao,1 Wayne C. Glasgow,2 John S. Penn,3 Dianna A. Johnson,4 and Gadiparthi N. Rao1

1From the Departments of Physiology and 4Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee; 2Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia; and 3Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, Tennessee.

PURPOSE. To examine for the expression of 15-lipoxygenase 1 (15-LOX1) and 15-LOX2 in human retinal microvascular endothelial cells (HRMVECs) and study the role of arachidonic acid metabolites of these enzymes in angiogenesis.

METHODS. Quantitative RT-PCR and reverse-phase HPLC analyses were used to determine 15-LOX1/2 expression and their arachidonic acid metabolites in HRMVECs. The role of MEK1 in 15(S)-HETE–induced angiogenesis was studied using HRMVEC migration, tube formation, and basement membrane matrix plug angiogenesis.

RESULTS. HRMVECs expressed both 15-LOX1 and 15-LOX2. Hypoxia induced the expression of 15-LOX1 and the production of its arachidonic acid metabolites 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) and 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). 15(S)-HETE stimulated HRMVEC migration and tube formation as potently as 20 ng/mL fibroblast growth factor-2 (FGF-2). In addition, 15(S)-HETE stimulated the phosphorylation of ERK1/2, JNK1, p38 MAPK, and MEK1 in a time-dependent manner in these cells. Inhibition of MEK1 by pharmacologic and dominant-negative mutant approaches attenuated 15(S)-HETE–induced phosphorylation of ERK1/2 and JNK1 but not p38 MAPK. Blockade of ERK1/2 and JNK1 activation suppressed 15(S)-HETE–induced HRMVEC migration and tube formation and basement membrane matrix plug angiogenesis. Inhibition of p38 MAPK attenuated 15(S)-HETE–induced HRMVEC migration only. Inhibition of MEK1 also blocked 15(S)-HETE–induced HRMVEC migration and tube formation and basement membrane matrix plug angiogenesis.

CONCLUSIONS. These results suggest that hypoxia, through the induction of 15-LOX1 expression, leads to the production of 15(S)-HETE in HRMVECs. In addition, 15(S)-HETE, through MEK1-dependent activation of ERK1/2 and JNK1, stimulates the angiogenic differentiation of HRMVECs and basement membrane matrix plug angiogenesis.






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