Targeting of Mitogen-Activated Protein Kinases and Phosphatidylinositol 3 Kinase Inhibits Hepatocyte Growth Factor/Scatter Factor–Induced Angiogenesis

Sengupta, Shiladitya; Sellers, Lynda A.; Li, Rung Chi; Gherardi, Ermanno; Zhao, Ganlin; Sasisekharan, Ram; Fan, Tai‐Ping

doi:10.1161/01.cir.0000077501.19266.e5

Cited by 29 publications

(24 citation statements)

References 25 publications

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“…We used hepatocyte growth factor/scatter factor (HGF/SF), a tyrosine kinase receptor ligand, as a chemoattractant in this study, and we have previously demonstrated that it is a potent and independent activator of the endothelium. 9,10 In this assay, although neither Rg1 nor Rb1 exerted any independent chemoattractant property, Rb1 inhibited the HGF/SF-induced chemoinvasion. In contrast, Rg1 was found to potentiate the chemoinvasion by the endothelial cells toward HGF/SF.…”

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confidence: 86%

Modulating Angiogenesis

et al. 2004

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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...

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Modulating Angiogenesis

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“…Early studies by Rosen and colleagues 33 established that SMC cultures produce HGF/SF and that endothelial cells (ECs) respond to the factor. 34 Subsequent studies revealed a major angiogenic activity for HGF/SF [35][36][37][38][39][40] although failing to detect MET expression 39 and/or a response to HGF/SF in SMCs. 41,42 These studies led to the view that, in the arterial wall, SMC-derived HGF/SF acts as a paracrine effector of ECs.…”

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Hepatocyte Growth Factor/Scatter Factor and MET Are Involved in Arterial Repair and Atherogenesis

McKinnon

Gherardi

Reidy

et al. 2006

The American Journal of Pathology

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Several studies have shown that in the arterial wall hepatocyte growth factor/scatter factor (HGF/SF) is expressed by smooth muscle cells (SMCs) but acts on endothelial cells, not SMCs. Other studies, however, have indicated that SMCs can respond to HGF/SF. We have reinvestigated expression and activity of HGF/SF and its receptor MET in arterial SMC and endothelial cell cultures and in whole arteries after superficial or deep injury or atherogenesis. High-density cultures of SMCs produced HGF/SF but did not express MET, whereas SMCs, at the leading edge of injured cultures, expressed both ligand and receptor and showed a dramatic motility and growth response to HGF/SF. In line with these results, HGF/SF and MET expression was undetectable in the media of uninjured carotid arteries but was induced after deep arterial injury in areas of SMC migration in the neointima. Strong MET expression was also observed in the SMCs of the atherosclerotic lesions of homozygous apoE ؊/؊ mice, whereas HGF/SF was expressed by macrophage-derived foam cells. These results demonstrate that MET is induced in migrating and proliferating SMCs and that HGF/SF and MET are key mediators of the SMC response in atherogenesis. (Am J

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“…We and others have previously demonstrated that HGF/SF can mount a strong angiogenic response (12), both independently of other growth factors (10) and by inducing expression of VEGF (31). Furthermore, a study to assess the safety of intramuscular injection of HGF/SF plasmid to improve limb perfusion in patients with critical limb ischemia (the HGF-STAT trial) has recently revealed that intramuscular injection of HGF plasmid was safe and well tolerated, and limb tissue perfusion as measured by transcutaneous oxygen tension in patients with critical limb ischemia was found to have significantly improved at the highest doses used (32).…”

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confidence: 91%

“…Hepatocyte growth factor/scatter factor (HGF/SF) is a potent angiogenic agent (10), signaling through the Met receptor and downstream MAPK and the PI3K pathways (11)(12). Interestingly, the Met receptor is upregulated during hypoxia, suggesting that the ischemic tissue will be primed for activation by HGF/SF (13).…”

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Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis

Roy

Soni

Harfouche

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate that nanoformulating 1K1 for sustained release temporally alters downstream signaling through the mitogen activated protein kinase pathway, and amplifies the angiogenic outcome. Merging protein engineering and nanotechnology offers exciting possibilities for the treatment of ischemic disease, and furthermore allows the selective targeting of downstream signaling pathways, which translates into discrete phenotypes.N eovascularization in the adult holds the potential for ameliorating ischemic disease, which is the leading cause of morbidity and mortality in the United States (1). Ferrara and Kerbel recently articulated that "therapeutic angiogenesis" is an emerging and exciting frontier of cardiovascular medicine (2). However, while early preclinical studies and phase I clinical trials exhibited promising results with recombinant proteins or gene therapy, more rigorous phase II and III studies have reported conflicting outcomes (3-6). A recent review of these clinical trials highlighted vector "washout" leading to inadequate duration of exposure to the angiogenic agent as a key factor that may have impaired the effectiveness of therapy (7). Indeed, it is now established that sustained activation of downstream signal pathways promotes cellular processes critical for angiogenesis (8). We rationalized that harnessing a nanotechnology-based approach can enable a temporal control over the presentation of the angiogenic factors to the cellular target, thereby altering the activation of downstream signal transduction.While nanoformulation of angiogenic proteins is an attractive strategy, the synthesis and instability of these large complex glycosylated structures pose a significant barrier (9). Hepatocyte growth factor/scatter factor (HGF/SF) is a potent angiogenic agent (10), signaling through the Met receptor and downstream MAPK and the PI3K pathways (11-12). Interestingly, the Met receptor is upregulated during hypoxia, suggesting that the ischemic tissue will be primed for activation by HGF/SF (13). These results indicate that HGF/SF could emerge as an attractive therapy for angiogenesis. However, HGF/SF is a heparin-binding protein with a complex multidomain structure consisting of an N-terminal (N) domain, four copies of the kringle domain (K1 to K4) and a C-terminal domain homologous to that of serine proteineases (SP) (Fig. 1A) (14). Biologically active HGF/SF is produced by proteolytic cleavage of the linker connecting the fourth kringle and the SP domain yielding a two-chain (α/β)-heterodimer, in which both the α-and the...

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Targeting of Mitogen-Activated Protein Kinases and Phosphatidylinositol 3 Kinase Inhibits Hepatocyte Growth Factor/Scatter Factor–Induced Angiogenesis

Cited by 29 publications

References 25 publications

Modulating Angiogenesis

Modulating Angiogenesis

Hepatocyte Growth Factor/Scatter Factor and MET Are Involved in Arterial Repair and Atherogenesis

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis

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