Angiogenic activity of sesamin through the activation of multiple signal pathways.
The natural product sesamin has been known to act as a potent antioxidant and prevent endothelial dysfunction. We here found that sesamin increased in vitro angiogenic processes, such as endothelial cell proliferation, migration, and tube formation, as well as neovascularization in an animal model. This compound elicited the activation of multiple angiogenic signal modulators, such as ERK, Akt, endothelial nitric oxide synthase (eNOS), NO production, FAK, and p38 MAPK, but not Src. The MEK inhibitor PD98059 and the PI3K inhibitor Wortmannin specifically inhibited sesamin-induced activation of the ERK and Akt/eNOS pathways. These inhibitors reduced angiogenic events, with high specificity for MEK/ERK-dependent cell proliferation and migration and PI3K/Akt-mediated tube formation. Moreover, inhibition of p38 MAPK effectively inhibited sesamin-induced cell migration. The angiogenic activity of sesamin was not associated with VEGF expression. Furthermore, this compound did not induce vascular permeability and upregulated ICAM-1 and VCAM-1 expression, which are hallmarks of vascular inflammation. These results suggest that sesamin stimulates angiogenesis in vitro and in vivo through the activation of MEK/ERK-, PI3K/Akt/eNOS-, p125(FAK)-, and p38 MAPK-dependent pathways, without increasing vascular inflammation, and may be used for treating ischemic diseases and tissue regeneration.
Chung
Byung-Hee
BH
Vascular System Research Center and Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, South Korea.
Lee
Jung Joon
JJ
Kim
Jong-Dai
JD
Jeoung
Dooil
D
Lee
Hansoo
H
Choe
Jongseon
J
Ha
Kwon-Soo
KS
Kwon
Young-Geun
YG
Kim
Young-Myeong
YM
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002478:Cells, Cultured; D004149:Dioxoles / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D005419:Flavonoids / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000096:biosynthesis; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D019061:src-Family Kinases / Q000096:biosynthesis
D000730:Androstadienes; D000975:Antioxidants; D015815:Cell Adhesion Molecules; D004149:Dioxoles; D005419:Flavonoids; D017705:Lignans; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C054125:sesamin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin