Published Online
on June 2, 2003

A more recent version of this article appeared on June 17, 2003

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Submitted on January 15, 2003
Revised on February 28, 2003
Accepted on March 1, 2003

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

Shiladitya Sengupta PhD^*, Lynda A. Sellers PhD, Rung-Chi Li MS, Ermanno Gherardi PhD, Ganlin Zhao MS, Nicki Watson BS, Ram Sasisekharan PhD, and Tai-Ping D. Fan PhD

From the Angiogenesis Laboratory (S.S., R.-C.L., T.-P.D.F.), Glaxo Institute of Applied Pharmacology (L.A.S.), Department of Pharmacology; Department of Oncology (E.G.), University of Cambridge, Cambridge, United Kingdom; and the Biological Engineering Division, M.I.T (S.S., G.Z., R.S.), Whitehead Institute (N.W.), Cambridge, Mass.

^* To whom correspondence should be addressed. E-mail: shiladit{at}MIT.edu.

Background--Hepatocyte growth factor/scatter factor (HGF/SF) can sufficiently and independently induce pathophysiological angiogenesis. However, the treatment strategies have mostly been unsuccessful. The present study is the first to evaluate the possible targeting of downstream signals for the inhibition of HGF/SF-induced angiogenesis.

Methods and Results--In a multichannel scratch assay with human endothelial cells (ECs), HGF/SF induced a strong and prolonged activation of MAPK and cell proliferation that was inhibited by PD98059 and LY294002/wortmannin, selective inhibitors of MAPK and PI3K signaling modules, respectively. Western blotting demonstrated a temporal relation between the activation of the two pathways. Chemical inhibition of the PI3K and MAPK signals inhibited HGF/SF-induced chemoinvasion of ECs in vitro and blocked the HGF/SF-induced neovascularization into a polymer scaffold in vivo, as quantified by vessel counts and the clearance of radioactive ¹³³Xe.

Conclusions--These data indicate that MEK and PI3K inhibitors represent a promising approach to the clinical management of pathological conditions characterized by overt HGF/SF-induced angiogenesis.

Key words: angiogenesis • growth substances • endothelium • signal transduction

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