Vascular Endothelial Growth Factor Receptor 2 Plays a Role in the Activation of Aortic Endothelial Cells by Oxidized Phospholipids

Abstract

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. Methods and Results-Ox-PAPC induced the phosphorylation of VEGFR2 at Tyr 1175 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.

Evidence for the importance of OxPAPC interaction with cysteines in regulating endothelial cell function

“…We examined the binding of OxPNB and its constituents to total HAEC protein and to a model protein, H-Ras. Ras is a central protein in cell signaling in infl ammatory pathways, including the activation of MAPK/ ERK and Akt pathways, which have both been reported by our group and others to be induced by OxPAPC ( 7,8 ). Furthermore, our group has reported that H-Ras has a role in the recruitment of monocytes to endothelial cells, an important initial event in atherogenesis (9)(10)(11).…”

Endothelial cell regulation by phospholipid oxidation products

“…In these studies, siRNA against VEGFR2 decreased the transcription of IL-8 and LDL receptor in response to Ox-PAPC, as well as decreasing the activation of SREBP ( 30 ). Furthermore, Ox-PAPC-induced VEGFR2 activation was c-Src dependent 30 , suggesting potential cross talk between the c-Src/JAK2/STAT3 pathway and the uncoupled eNOS/SREBP pathway. While a role for VEGFR2 in Ox-PAPC induced eNOS activation and uncoupling was not reported, other studies have reported interaction between VEGFR2 and eNOS 31 .…”

“…L-NAME, an inhibitor of eNOS activity, was able to partially inhibit SREBP activation and the expression of known SREBP target genes, such as the LDL receptor ( 28 ), by Ox-PAPC. Furthermore, recent findings have also demonstrated a role for VEGFR2 in these pathways 30 . In these studies, siRNA against VEGFR2 decreased the transcription of IL-8 and LDL receptor in response to Ox-PAPC, as well as decreasing the activation of SREBP ( 30 ).…”

“…In a separate study, VEGFR2 was demonstrated to regulate ERK activation and TF expression. 30 Thus, VEGFR2 appears to be an important receptor in the regulation of inflammation and coagulation. The mechanism mediating the reduction in TM mRNA levels by Ox-PAPC has also been examined.…”

Inflammation-related gene expression by lipid oxidation-derived products in the progression of atherosclerosis

“…In addition, up-regulation of VEGF induces expression of VCAM-1 and platelet endothelial cell adhesion molecule (PECAM-1) on the endothelium, and stimulates monocyte adhesion, leading to the formation of more inflamed atherosclerotic lesions in ApoE -/-mice [196]. Again, in human aortic ECs, VEGF receptor 2 is reported to regulate ERK1/2-mediated activation of the transcription factor sterol regulatory element-binding protein 1 (SREBP-1), and the subsequent transcription of tissue factor, LDL receptor, and IL-8 [197]. Endothelial NOS has been reported to play a role in the activation of SREBP by oxPAPC [198].…”