Macrophage expression of VEGF and VEGFR-1. Potential involvement in atherogenesis

Abstract: The vascular endothelial growth factor (VEGF) family is a group of proteins which contributes to both neovascularisation and inflammation. Elevated levels of VEGF have been found in subjects with atherosclerosis and correlate to several cardiovascular risk factors, e.g. hypertension and hyperlipidemia. The pro-atherogenic effects of VEGF are implied to be due to its ability to increase infiltration of monocytes into atherosclerotic lesions and to induce plaque neovascularisation. Atherosclerotic plaques that are prone to rupture are composed of a large amount of macrophages and lipids. They are also characterised by neovascularisation. Plaque rupture and the subsequent blood clot formation is the most common underlying cause of heart attack or stroke.VEGF-signalling is mediated by two receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). The pro-angiogenic properties of VEGF are mainly mediated through VEGFR-2, while the role of VEGFR-1 is more elusive. VEGFR-1 is suggested to be a ligand-binding molecule, negatively regulating the levels of VEGF. However, VEGFR-1 is the main VEGF receptor expressed on monocytes/macrophages. It is thereby considered to be the mediator of VEGF-induced infiltration of these cells into atherosclerotic lesions. In this thesis we detected that human monocyte-derived macrophages express VEGF, VEGF-B, VEGFR-1 and VEGFR-2. Oxidative modifications of lipoproteins are considered a key factor in initiation and progression of atherosclerosis. Interestingly, we observed that oxidised LDL (oxLDL) increased expression of VEGF at the same time as it decreased expression of VEGFR-1. The expression of the remaining factors in the VEGF family was unaltered. In addition, oxLDL activated the redox sensitive p38 MAPK intracellular signalling pathway. The upregulation of VEGF was mediated by a p38 MAPK-independent stabilisation of its mRNA but also by a p38 MAPK-dependent mechanism, probably acting at the transcriptional level. OxLDL downregulated VEGFR-1 expression through a transcriptional mechanism, involving a PPARg-dependent inhibition of binding of the transcription factor AP-1 to the VEGFR-1 promoter. Moreover, the effect of statins on plasma levels of VEGF and sVEGFR-1 was studied in hyperlipidemic subjects. Both atorvastatin and simvastatin treatment decreased plasma levels of these two factors. In conclusion, inducing VEGF and reducing VEGFR-1 expression in macrophages may be an additional way for oxLDL to contribute to atherosclerotic plaque formation. Increased VEGF expression by macrophages inside the plaque may increase monocyte migration into lesions from the circulation. It is also possible that a decrease in the negative regulator VEGFR-1 makes more VEGF available for binding to VEGFR-2. The consequence of this binding may be increased plaque vascularisation. Finally, the beneficial effects of statins on plaque progression and their protective role on the endothelium may in part be a result of decreased VEGF and sVEGFR-1 levels in the circulation.