[Arachidonic acid epoxygenases and their metabolites promote angiogenesis].
OBJECTIVE
To investigate the angiogenetic effects of endogenous and exogenous epoxyeicosatrienoic acids (EET) and the relevant signaling mechanisms involved.


METHODS
Bovine aortic endothelial cells (BAEC) were incubated with synthetic EETs or infected with recombinant adeno-associated viruses (rAAV) containing CYP2C11-CYPOR, CYP2J2 or CYP102 F87V mutant to increase endogenous expression levels of EETs. BAEC proliferation measured by cell counting and chromatometry, migration assessed by transwell analysis, and capillary formation determined by chicken embryo chorioallantoic membrane assays (CAM) and tube formation tests on matrigel and angiogenesis were analysed in vivo. The potential involvement of various signaling pathways were explored using selective inhibitors.


RESULTS
Transfection with rAAV-2C11OR, rAAV-2J2 or rAAV-F87V promoted BAEC proliferation, migration, and capillary tubule formation. However, 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 endothelial nitric oxide synthase (eNOS) inhibitor, but not by a protein kinase C inhibitor. In a rat ischemic hind limb model, rAAV-mediated epoxygenase transfection induced angiogenesis.


CONCLUSIONS
Arachidonic acid epoxygenase and its metabolites can promote angiogenesis through activating MAPK and PI3 kinase/Akt signaling pathways, and to some extent, the eNOS pathway, and the angiogenic effects may provide protection to ischemic tissues.
Wang
Yan
Y
The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Wang
Jia-ning
JN
Liu
Zhen-jun
ZJ
Wei
Xin
X
Xiao
Xiao
X
Wang
Dao-wen
DW
D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014162:Transfection
D015126:8,11,14-Eicosatrienoic Acid; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C000717350:CYP2J2 protein, human