Vascular endothelial growth factor (
VEGF) plays a key role in angiogenesis, but
VEGF-induced angiogenesis is often accompanied by a vascular permeability response.
Ginsenosides are
triterpenoid saponins from the well-known medicinal plant, ginseng, and have been considered a candidate for modulating angiogenesis. Here, we systemically investigated the effects of 10 different
ginsenosides on human umbilical vein endothelial cells and newly identified that two PPT-type
ginsenosides, F1 and Rh1 induce the migration and proliferation of endothelial cells. Interestingly,
RNA transcriptome analysis showed that gene regulation induced by
VEGF in endothelial cells is distinct from that of
ginsenoside F1 and Rh1. In addition, F1 and Rh1 significantly inhibited vascular leakage both in vitro and in vivo, which are induced by
vascular endothelial growth factor. Furthermore, comparative transcriptome analysis revealed that these effects of F1 and Rh1 on vascular leakage restoration are mainly caused by changes in
VEGF-mediated TNFα signaling via NFκB, particularly by the suppression of expression and transcriptional activity of NR4A1 by F1 and Rh1, even in the presence of
VEGF. These findings demonstrate that
ginsenosides F1 and Rh1 can be a promising herbal remedy for vessel normalization in ischemic disease and
cancer and that NR4A1 is the key target.