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(Circulation. 2004;110:1219-1225.)
© 2004 American Heart Association, Inc.

Original Articles

Modulating Angiogenesis

The Yin and the Yang in Ginseng

Shiladitya Sengupta, PhD; Sue-Anne Toh, MBChB; Lynda A. Sellers, PhD; Jeremy N. Skepper, PhD; Pieter Koolwijk, PhD; Hi Wun Leung, PhD; Hin-Wing Yeung, PhD; Ricky N.S. Wong, PhD; Ram Sasisekharan, PhD; Tai-Ping D. Fan, PhD

From the Angiogenesis Laboratory, Department of Pharmacology (S.S., S.-A.T., L.A.S., T.-P.D.F.), and Multi-imaging Centre, Department of Anatomy (J.N.S.), University of Cambridge, Cambridge, UK; Gaubius Laboratory, TNO-PG, Leiden, the Netherlands (P.K.); Research and Development Division, School of Chinese Medicine, Hong Kong Baptist University, Kownloon, Hong Kong, China (H.W.L., H.-W.Y., R.N.S.W.); and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge (S.S., R.S.).

Correspondence to Shiladitya Sengupta, PhD, Biological Engineering Division, 16-561, Massachusetts Institute of Technology, Cambridge, MA 02139 (e-mail shiladit{at}MIT.edu), or Tai-Ping D. Fan, PhD, Angiogenesis Laboratory, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, UK CB2 1PD, United Kingdom (e-mail tpf1000@cam.ac.uk).

Received April 9, 2003; de novo received January 2, 2004; revision received February 19, 2004; accepted April 16, 2004.

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 kinaseAkt 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 • angiogenesis • nitric oxide

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