Vascular endothelial growth factor receptor 2 plays a role in the activation of aortic endothelial cells by oxidized phospholipids.
OBJECTIVE
Previous studies have shown that oxidized products of PAPC (Ox-PAPC) regulate cell transcription of interleukin-8, LDL receptor, and tissue factor. This upregulation takes place in part through the activation of sterol regulatory element-binding protein (SREBP) and Erk 1/2. The present studies identify vascular endothelial growth factor receptor 2 (VEGFR2) as a major regulator in the activation of SREBP and Erk 1/2 in endothelial cells activated by Ox-PAPC.


RESULTS
Ox-PAPC induced the phosphorylation of VEGFR2 at Tyr1175 in human aortic endothelial cells. Inhibitors and siRNA for VEGFR2 decreased the transcription of interleukin-8, LDL receptor, and tissue factor in response to Ox-PAPC and the activation of SREBP and Erk 1/2, which mediate this transcription. We provide evidence that the activation of VEGFR2 is rapid, sustained, and c-Src-dependent.


CONCLUSIONS
These data point to a major role of VEGFR2 in endothelial regulation by oxidized phospholipids which accumulate in atherosclerotic lesions and apoptotic cells.
Zimman
Alejandro
A
Departments of Medicine, University of California, Los Angeles, CA, USA.
Mouillesseaux
Kevin P
KP
Le
Thang
T
Gharavi
Nima M
NM
Ryvkin
Ann
A
Graeber
Thomas G
TG
Chen
Tom T
TT
Watson
Andrew D
AD
Berliner
Judith A
JA
D002460:Cell Line; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000502:physiology; D010713:Phosphatidylcholines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000502:physiology; D013925:Thromboplastin / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
D016209:Interleukin-8; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D051779:Sterol Regulatory Element Binding Proteins; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D013925:Thromboplastin; D040301:Vascular Endothelial Growth Factor Receptor-2; D048052:Mitogen-Activated Protein Kinase 3