Vascular endothelial growth factor downregulates apolipoprotein M expression by inhibiting Foxa2 in a Nur77-dependent manner.

OBJECTIVE

We aimed to investigate whether vascular endothelial growth factor (VEGF) influences apolipoprotein M (ApoM) expression and pre-β-high-density lipoprotin (HDL) formation, and whether forkhead box A2 (Foxa2) and Nur77 are involved in this process.

METHODS AND RESULTS

We analyzed the serum VEGF concentrations of 264 adults who underwent a medical checkup and found that VEGF concentration was positively correlated with serum triglyceride, total cholesterol, LDL cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), and ApoB concentrations, but was negatively correlated with serum high-density lipoprotein cholesterol (HDL-C) and ApoM concentrations. We further investigated the effects of VEGF on ApoM expression and pre-β-HDL formation, and the mechanisms responsible, in HepG2 cells and mouse primary hepatocytes. VEGF markedly downregulated ApoM expression and pre-β-HDL formation. At the same time, expression of Foxa2 was also inhibited, whereas expression of Nur77 was increased by treatment with VEGF. Furthermore, small interfering (si) RNA knockdown of Foxa2 made the downregulation of VEGF on ApoM expression and pre-β-HDL formation even more obvious. In addition, siRNA knockdown of Nur77 significantly compensated for the inhibitory effect of VEGF on Foxa2 expression, whereas the Nur77 agonist cytosporone B led to the downregulation of Foxa2 expression more significantly than VEGF. Moreover, overexpression of a Nur77 transgene in C57BL/6 mice resulted in decreased serum ApoM and pre-β-HDL levels, whereas si-Nur77-treated mice displayed upregulated serum ApoM and pre-β-HDL levels.

CONCLUSION

These results provide evidence that VEGF may first downregulate expression of Foxa2 by enhancing Nur77 activity and then decrease expression of ApoM and pre-β-HDL formation. Therefore, our study may be useful in understanding the critical effect of VEGF in the pathogenesis of atherosclerosis.