Water extract of Korean red ginseng stimulates angiogenesis by activating the PI3K/Akt-dependent ERK1/2 and eNOS pathways in human umbilical vein endothelial cells.
Angiogenesis is important for promoting cardiovascular disease, wound healing, and tissue regeneration. We investigated the effects of Korean red ginseng water extract (KRGE) on angiogenesis and its underlying signal mechanism. KRGE increased in vitro proliferation, migration, and tube formation of human umbilical vein endothelial cells, as well as stimulated in vivo angiogenesis without increasing VEGF expression. KRGE-induced angiogenesis was accompanied by phosphorylation of ERK1/2, phosphatidylinositol 3-kinase (Akt), and endothelial nitric oxide synthase (eNOS) as well as an increase in NO production. Inhibition of PI3K activity by wortmannin completely inhibited KRGE-induced angiogenesis and phosphorylation of Akt, ERK1/2, and eNOS, indicating that PI3K/Akt activation is an upstream event of the KRGE-mediated angiogenic pathway. The MEK inhibitor PD98059 blocked KRGE-induced ERK1/2 phosphorylation without affecting Akt and eNOS activation. However, the eNOS inhibitor N(G)-monomethyl-L-arginine effectively inhibited tube formation, but partially blocked proliferation and migration as well as ERK phosphorylation, without altering Akt and eNOS activation, revealing that the eNOS/NO pathway is partially involved in ERK1/2 activation. This study demonstrated that KRGE stimulates in vitro and in vivo angiogenesis through the activation of the PI3K/Akt-dependent ERK1/2 and eNOS signal pathways and their cross talk.
Kim
Young-Mi
YM
Vascular System Research Center and Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon, Kangwon-do 200-701, Korea.
Namkoong
Seung
S
Yun
Young-Gab
YG
Hong
Hee-Do
HD
Lee
Young-Chul
YC
Ha
Kwon-Soo
KS
Lee
Hansoo
H
Kwon
Ho Jeong
HJ
Kwon
Young-Guen
YG
Kim
Young-Myeong
YM
D000818:Animals; D015153:Blotting, Western; D002633:Chemotaxis / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000502:physiology*; D005894:Panax / Q000737:chemistry*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D012997:Solvents; D013268:Stimulation, Chemical; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D014867:Water