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Received for publication January 14, 2005.
Revised April 14, 2005.
Accepted for publication April 15, 2005.
Cytochrome P450 arachidonic acid (AA) epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs), dilate arteries via hyperpolarization of smooth muscle cells and also have non-vasodilatory effects within the vasculature. The present study investigated the angiogenenic 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 (rAAV) containing CYP2C11-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 (CAM) 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-kinase (PI3 kinase)/Akt pathways, and partially attenuated by an eNOS inhibitor, but not by a protein kinase C (PKC) 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.
Key words:
Arachidonic acid, angiogenesis, bovine aorta endothelial cells, cell signaling, cytochrome p450 epoxygenase-derived Eicosanoids, recombinant adeno-associated virus mediated gene expression
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