Aggretin, a snake venom-derived endothelial integrin alpha 2 beta 1 agonist, induces angiogenesis via expression of vascular endothelial growth factor.
Aggretin, a collagen-like alpha 2 beta 1 agonist purified from Calloselasma rhodostoma venom, was shown to increase human umbilical vein endothelial cell (HUVEC) proliferation and HUVEC migration toward immobilized aggretin was also increased. These effects were blocked by A2-IIE10, an antibody raised against integrin alpha 2. Aggretin bound to HUVECs in a dose-dependent and saturable manner, which was specifically inhibited by A2-IIE10, as examined by flow cytometry. Aggretin elicited significant angiogenic effects in both in vivo and in vitro angiogenesis assays, and incubation of HUVECs with aggretin activated phosphatidylinositol 3-kinase (PI3K), Akt, and extracellular-regulated kinase 1/2 (ERK1/2); these effects were blocked by A2-IIE10 or vascular endothelial growth factor (VEGF) monoclonal antibody (mAb). The angiogenic effect induced by aggretin may be via the production of VEGF because the VEGF level was elevated and VEGF mAb pretreatment inhibited Akt/ERK1/2 activation as well as the in vivo angiogenesis induced by aggretin. The VEGF production induced by aggretin can be blocked by A2-IIE10 mAb pretreatment. In conclusion, aggretin induces endothelial cell proliferation, migration, and angiogenesis by interacting with integrin alpha 2 beta 1 leading to activation of PI3K, Akt, and ERK1/2 pathways, and the increased expression of VEGF may be responsible for its angiogenic activity.
Chung
Ching-Hu
CH
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Wu
Wen-Bin
WB
Huang
Tur-Fu
TF
D001672:Biocompatible Materials; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000819:agonists*; D007797:Laminin; D037181:Lectins, C-Type / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D011509:Proteoglycans; D015398:Signal Transduction / Q000187:drug effects; D012910:Snake Venoms / Q000737:chemistry; D014471:Umbilical Veins / Q000166:cytology; D014757:Viper Venoms / Q000378:metabolism / Q000494:pharmacology*
D001672:Biocompatible Materials; D004338:Drug Combinations; D038982:Integrin alpha2beta1; D007797:Laminin; D037181:Lectins, C-Type; D011509:Proteoglycans; D012910:Snake Venoms; D014757:Viper Venoms; C112292:rhodocytin protein, Calloselasma rhodostoma; C059485:matrigel; D003094:Collagen; D011494:Protein Kinases