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. Methods and 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 kinase3 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. Key Words: ginsenosides Ⅲ angiogenesis Ⅲ nitric oxide T he use of botanicals as alternative medicine has seen a resurgence of use in the United States and Europe. In 2001, $17.8 billion was spent on dietary supplements, $4.2 billion of it for herbal remedies. 1 It is estimated that Ͼ12.1% of adults in the United States used herbal medicines in 1997. 2 Interestingly, in the United States, herbal medicines are regulated as dietary supplements and fall under the purview of the 1994 Dietary Supplement and Health Education Act (DSHEA) and thus can be marketed without prior approval by the Food and Drug Administration (FDA). 3 Ginseng is a key component in traditional Chinese medicine and is also one of the most extensively used botanical products in the West, which is evident from annual sales of US $0.225 to $0.3 billion. 4 Named by the botanist Carl Meyer, the genus Panax derives its name from the Greek pan (all) and akos (healing). 4 The activity of ginseng extract has been studied extensively. Ambiguously, ginseng extract has been reported to promote wound healing 5 and inhibit tumor growth 6,7 through opposing effects on angiogenesis. To elucidate this perplexity in...
