Induction of Macrophage VEGF in Response to Oxidized LDL and VEGF Accumulation in Human Atherosclerotic Lesions

Abstract

Abstract-The interaction between macrophages and oxidatively modified low density lipoprotein (Ox-LDL) appears to play a central role in the development of atherosclerosis, not only through foam cell formation but also via the induction of numerous cytokines and growth factors. The current study demonstrated that Ox-LDL upregulated vascular endothelial growth factor (VEGF) mRNA expression in RAW 264 cells, a monocytic cell line, in a time-and concentration-dependent manner and that Ox-LDL stimulated VEGF protein secretion from the cells. Lysophosphatidylcholine, a component of Ox-LDL, also enhanced VEGF mRNA expression in RAW 264 cells and VEGF secretion from RAW 264 cells, with a maximal effect at a concentration of 10 mol/L lysophosphatidylcholine. Immunohistochemical studies showed that human early atherosclerotic lesions exhibited intense VEGF immunoreactivity in subendothelial macrophage-rich regions of the thickened intima. In atherosclerotic plaques, VEGF staining was also observed in foam cell-rich regions adjacent to the lipid core or the neovascularized basal regions of plaque consisting predominantly of smooth muscle cells. High-power-field observation revealed that VEGF was localized in the extracellular space as well as at the macrophage cell surface. These observations suggest the possible involvement of Ox-LDL in the development of human atherosclerosis through VEGF induction in macrophages. (Arterioscler Thromb

Oxidized LDL Regulates Vascular Endothelial Growth Factor Expression in Human Macrophages and Endothelial Cells Through Activation of Peroxisome Proliferator–Activated Receptor-γ

“…Ramos et al 6 have shown that LPC also upregulates VEGF expression in RAW 264 cells. We have observed that LPC also induces VEGF expression in HCAECs.…”

“…Because Ox-LDL is abundant in atherosclerotic arterial walls and is critically involved in atherogenesis, we hypothesized that Ox-LDL might have a role in the expression of VEGF in atherosclerotic lesions. Ramos et al 6 have previously reported the induction of VEGF expression in a mouse macrophage-like cell line (RAW 264 cells) in response to Ox-LDL. The present study was compatible with their result and further revealed that Ox-LDLinduced upregulation of VEGF occurred not only in macrophages but also in endothelial cells.…”

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

“…VEGF is a pleiotropic growth factor that seems to play a role in atherogenesis. It was shown that VEGF could participate in the progression of atherosclerosis by promoting macrophage chemotaxis 39) ; however, its activity was strongly related to plaque neovascularization, increasing vessel permeability and the promotion of inflammatory cell infiltration via new vessels into atherosclerotic plaque 27) . These effects of VEGF were not observed in our study, because no angiogenesis or neovascularization was detected in the vessel wall.…”

Human endometrial angiogenesis

“…Other leucocytes, such as monocytes and T lymphocytes, produce VEGF when activated (Freeman et al, 1995;Harmey Human endometrial angiogenesis et al, 1998). There is evidence that in angiogenesis associated with inflammatory conditions, atherosclerosis and malignancy, extravasated leucocytes are a source of VEGF (Taichman et al, 1997;Harmey et al, 1998;Ramos et al, 1998). It is therefore possible that focal VEGF observed in human endometrium is located in intravascular leucocytes, which may have a role in endometrial angiogenesis by delivering VEGF directly to endothelial cells in vessels undergoing angiogenesis by non-sprouting mechanisms.…”