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CARDIOVASCULAR

Arachidonic Acid Epoxygenase Metabolites Stimulate Endothelial Cell Growth and Angiogenesis via Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways

The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (Y.W., X.W., X.X., D.W.W.); Departments of Molecular Genetics and Biochemistry and Gene Therapy Center, University of Pittsburgh, Pittsburgh, Pennsylvania (X.X.); Sino-German Laboratory for Molecular Medicine and Center for Molecular Cardiology, Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China (R.H.); and Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.W.C., M.A.C., D.C.Z.)

Cytochrome P450 arachidonic acid (AA) epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs), dilate arteries via hyperpolarization of smooth muscle cells and also have nonvasodilatory effects within the vasculature. The present study investigated the angiogenic effects of endogenous and exogenous EETs and the relevant signaling mechanisms involved. Bovine aortic endothelial cells (BAECs) were incubated with synthetic EETs or infected with recombinant adeno-associated viruses (rAAVs) containing CYP2C11-NADPH-cytochrome P450 oxidoreductase (CYPOR), CYP2J2, or CYP102 F87V mutant to increase endogenous levels of EETs. The following endpoints were measured: BAEC proliferation, migration, capillary formation, and in vivo angiogenesis. The potential involvement of various signaling pathways was explored using selective inhibitors. The results showed that transfection with either rAAV-CYP2C11-CYPOR, rAAV-CYP2J2, or rAAV-CYP102 F87V, or incubation with EETs promoted BAEC proliferation, increased migration of BAECs as assessed by Transwell analysis and wound healing assays, and enhanced capillary tubule formation as determined by chicken embryo chorioallantoic membrane assays and tube formation tests on matrigel. The effects of EETs on proliferation, migration, and capillary tubule formation were attenuated by inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 (PI3)-kinase/Akt pathways and partially attenuated by an endothelial nitricoxide synthase (eNOS) inhibitor but not by a protein kinase C inhibitor. In a rat ischemic hind limb model, rAAV-mediated AA epoxygenase transfection induced angiogenesis. We conclude that AA epoxygenase metabolites can promote angiogenesis, which may provide protection to ischemic tissues. The results also suggest that the angiogenic effects of EETs involve the MAPK and PI3-kinase/Akt signaling pathways, and to some extent, the eNOS pathway.

Address correspondence to: Dr. Dao Wen Wang, The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, People's Republic of China. E-mail: dwwang{at}tjh.tjmu.edu.cn

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