Abstract
Macrophages are largely involved in the whole process of atherosclerosis from an initiation lesion to an advanced lesion. Endothelial disruption is the initial step and macrophage-derived foam cells are the hallmark of atherosclerosis. Promotion of vascular integrity and inhibition of foam cell formation are two important strategies for preventing atherosclerosis. How can we inhibit even the reverse negative role of macrophages in atherosclerosis? The present study was performed to investigate if overexpressing endogenous human vascular endothelial growth factor (VEGF) could facilitate transdifferentiation of macrophages into endothelial-like cells (ELCs) and inhibit foam cell formation. We demonstrated that VEGF-modified macrophages which stably overexpressed human VEGF (hVEGF165) displayed a high capability to alter their phenotype and function into ELCs in vitro. Exogenous VEGF could not replace endogenous VEGF to induce the transdifferentiation of macrophages into ELCs in vitro. We further showed that VEGF-modified macrophages significantly decreased cytoplasmic lipid accumulation after treatment with oxidized LDL (ox-LDL). Moreover, down-regulation of CD36 expression in these cells was probably one of the mechanisms of reduction in foam cell formation. Our results provided the in vitro proof of VEGF-modified macrophages as atheroprotective therapeutic cells by both promotion of vascular repair and inhibition of foam cell formation.
Highlights
Atherosclerosis is the primary cause of mortality and morbidity in cardiovascular disease, which is the leading cause of deaths in industrialized society [1,2]
The vascular endothelial growth factor (VEGF)-treated RAW264.7 cultured at 50 ng/ml for 48 h was another control to determine whether exogenous recombinant hVEGF165 could replace the endogenous protein and have a similar effect. qRT-PCR analysis indicated that in hVEGF165-ZsGreen1-RAW264.7 cells compared with other groups, the expression of endothelial marker genes, such as fetal liver kinase 1 (FLK-1), von Willebrand factor (vWF), endothelial NO synthase (eNOS), VE-cadherin and Tie-2, were dramatically increased by 11-fold, 48-fold, 13-fold, 10-fold, and 13-fold, respectively (Figure 1A)
Macrophages are crucially involved in the whole process of atherosclerosis from early atherogenesis to advanced plaque progression [14,19,20]
Summary
Atherosclerosis is the primary cause of mortality and morbidity in cardiovascular disease, which is the leading cause of deaths in industrialized society [1,2]. It is generally recognized that endothelial dysfunction or disruption is the initial process of atherosclerosis [3,4,5]. Maintenance of the endothelial homeostasis and integrity by promoting early repair is an important strategy for preventing atherosclerosis [9,10]. Monocytes are recruited from peripheral blood and attach to the activated/damaged endothelium, migrate to subendothelial space and differentiate into macrophages. The uptake of oxidized LDL (ox-LDL) by monocyte-derived macrophage induces foam cell formation, which is a hallmark of the development of atherosclerosis [11,12]. Inhibition of foam cell formation in early stage is another fascinating approach for the prevention of progression of atherosclerosis
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