Modulating angiogenesis: the yin and the yang in ginseng.
BACKGROUND
Ginseng is a commonly used nutraceutical. Intriguingly, existing literature reports both wound-healing and antitumor effects of ginseng extract through opposing activities on the vascular system. To elucidate this perplexity, we merged a chemical fingerprinting approach with a deconstructional study of the effects of pure molecules from ginseng extract on angiogenesis.


RESULTS
A mass spectrometric compositional analysis of American, Chinese and Korean, and Sanqi ginseng revealed distinct "sterol ginsenoside" fingerprints, especially in the ratio between a triol, Rg1, and a diol, Rb1, the 2 most prevalent constituents. Using a Matrigel implant model and reconstituting the extracts using distinct ratios of the 2 ginsenosides, we demonstrate that the dominance of Rg1 leads to angiogenesis, whereas Rb1 exerts an opposing effect. Rg1 also promoted functional neovascularization into a polymer scaffold in vivo and the proliferation of, chemoinvasion of, and tubulogenesis by endothelial cells in vitro, an effect mediated through the expression of nitric oxide synthase and the phosphatidylinositol-3 kinase-->Akt pathway. In contrast, Rb1 inhibited the earliest step in angiogenesis, the chemoinvasion of endothelial cells.


CONCLUSIONS
The present study explains, for the first time, the ambiguity about the effects of ginseng in vascular pathophysiology based on the existence of opposing active principles in the extract. We also unraveled a speciogeographic variation impinging on the compositional fingerprint that may modulate the final phenotype. This emphasizes the need for regulations standardizing herbal therapy, currently under the Dietary Supplement and Health Education Act. Furthermore, we propose that Rg1 could be a prototype for a novel group of nonpeptide molecules that can induce therapeutic angiogenesis, such as in wound healing.
Sengupta
Shiladitya
S
Angiogenesis Laboratory, Department of Pharmacology, University of Cambridge, Cambridge, UK. shiladit@MIT.edu
Toh
Sue-Anne
SA
Sellers
Lynda A
LA
Skepper
Jeremy N
JN
Koolwijk
Pieter
P
Leung
Hi Wun
HW
Yeung
Hin-Wing
HW
Wong
Ricky N S
RN
Sasisekharan
Ram
R
Fan
Tai-Ping D
TP
D000569:Americas; D043925:Angiogenesis Inducing Agents / Q000737:chemistry / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D002681:China; D004343:Drug Implants; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D036145:Ginsenosides / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D007723:Korea; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000139:chemically induced; D005894:Panax / Q000737:chemistry* / Q000145:classification; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D008517:Phytotherapy / Q000592:standards; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization; D015503:Surgical Sponges / Q000009:adverse effects; D014471:Umbilical Veins
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D004343:Drug Implants; D004791:Enzyme Inhibitors; D036145:Ginsenosides; C442759:ginsenoside Rb1; D019869:Phosphatidylinositol 3-Kinases; C035054:ginsenoside Rg1; D019331:NG-Nitroarginine Methyl Ester