Grape seed proanthocyanidins inhibit angiogenesis via the downregulation of both vascular endothelial growth factor and angiopoietin signaling.
Vascular endothelial growth factor (VEGF)/VEGF receptor 2 and angiopoietin 1/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 signaling pathways regulate different, but complementary, aspects of blood vessel growth in tumors. Simultaneous inhibition of both pathways not only exhibits additive antiangiogenic effects but also overcomes the resistance to anti-VEGF therapy. Grape seed proanthocyanidins (GSPs) are widely consumed dietary supplements with antiangiogenic activity. However, the molecular mechanisms underlying their antiangiogenic action have not been fully understood. We hypothesized that GSPs modulate multiple signaling pathways to exhibit antiangiogenic effects. In the present study, we aimed to test this hypothesis by examining the effects of GSPs on human microvascular endothelial cell-1 and chick chorioallantoic membrane. Our results showed that GSPs inhibited the migration, matrix metalloproteinase-2 and -9 secretion, and tube formation of human microvascular endothelial cell-1 in vitro in a dose-dependent manner. In addition, chick chorioallantoic membrane angiogenesis assay showed that GSPs inhibited neovascularization in a dose-dependent manner. Furthermore, we demonstrated that GSPs inhibited the phosphorylation of VEGF receptor 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 as well as downstream signaling component extracellular signal-regulated kinase 1/2. In summary, these data suggest that GSPs inhibit both VEGF and angiopoietin 1 signaling to execute the antiangiogenic effects and indicate that GSPs could be developed as a pharmacologically safe chemopreventive agent against cancer.
Medical College of Northwest University for Nationalities, Lanzhou 730030, China. huangshsh02@qq.com
Shuangsheng
S
Huang
Ninggang
N
Yang
Yuanyuan
Y
Liu
Lamei
L
Hu
Jin
J
Zhao
Jing
J
Gao
Yongquan
Y
Li
Caili
C
Li
Xiaosu
X
Zhang
Tao
T
Huang
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D056604:Grape Seed Extract / Q000494:pharmacology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D044945:Proanthocyanidins / Q000494:pharmacology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D044945:Proanthocyanidins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D048052:Mitogen-Activated Protein Kinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9