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.
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.
Authors: Jinjing Zhao; Weiye Wang; Chang Hoon Ha; Ji Young Kim; Chelsea Wong; Eileen M Redmond; Anne Hamik; Mukesh K Jain; Gen-Sheng Feng; Zheng Gen Jin Journal: Arterioscler Thromb Vasc Biol Date: 2011-03-03 Impact factor: 8.311
Authors: Rituparna Sinha Roy; Shivani Soni; Rania Harfouche; Pooja R Vasudevan; Oliver Holmes; Hugo de Jonge; Arthur Rowe; Abhimanyu Paraskar; Dirk M Hentschel; Dimitri Chirgadze; Tom L Blundell; Ermanno Gherardi; Raghunath A Mashelkar; Shiladitya Sengupta Journal: Proc Natl Acad Sci U S A Date: 2010-07-16 Impact factor: 11.205