on November 21, 2002
Published online before print November 21, 2002, doi: 10.1161/01.ATV.0000048701.86621.D0
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Submitted on October 7, 2002
Accepted on October 28, 2002
Hepatocyte Growth Factor/Scatter Factor Can Induce Angiogenesis Independently of Vascular Endothelial Growth Factor
Shiladitya Sengupta *;
From the Angiogenesis Laboratory, Department of Pharmacology (S.S., T.-P.D.F.), the Department of Oncology (E.G.), and the Glaxo Institute of Applied Pharmacology (L.A.S.), University of Cambridge, Cambridge, England; the Angiogenesis Platform (J.M.W.), Novartis Pharma AG, Basel, Switzerland; and the Biological Engineering Division (S.S., R.S.), Massachusetts Institute of Technology, Cambridge, Mass.
* To whom correspondence should be addressed. E-mail: shiladit{at}MIT.edu.
Objective—Hepatocyte growth factor/scatter factor (HGF/SF) promotes vascular endothelial growth factor (VEGF) expression and induces angiogenesis in multiple pathological conditions. The present study was designed to delineate the HGF/SF and VEGF signaling cascades during angiogenesis by using PTK787, a selective VEGF receptor antagonist.
Methods and Results—PTK787 produced a concentration-dependent (10-8 to 10-6 mol/L) inhibition of VEGF-induced angiogenesis, without altering the basal or HGF/SF-induced response in vitro. In contrast, the nonspecific kinase inhibitor genistein blocked the HGF/SF-induced effect. Both VEGF and HGF/SF induced a rapid phosphorylation of extracellular receptor kinases-1 and -2 (ERKs) and Akt. PTK787 inhibited the VEGF-induced activation of Akt and ERKs, without affecting the HGF/SF-induced phosphorylation. Treatment with VEGF and HGF/SF increased total neovascularization in a murine scaffold granuloma model, but no additive or synergistic interactions were observed. PTK787 (50 mg/kg) blocked the VEGF-induced response without altering the basal or HGF/SF-induced neovascularization.
Conclusions—We demonstrate that HGF/SF can induce angiogenesis independently of VEGF, possibly through the direct activation of the Akt and ERKs. These results demonstrate the necessity of a multitargeted approach for the rational design of newer therapies to inhibit pathophysiological angiogenesis.
Key words: hepatocyte growth factor/scatter factor • vascular endothelial growth factor • angiogenesis • PTK787
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