Anti-angiogenic activity of contortrostatin, a disintegrin from Agkistrodon contortrix contortrix snake venom.
Previous work in our laboratory has shown that contortrostatin (CN), a disintegrin from southern copperhead snake venom, possess anti-angiogenic activity. In the present study we further examined the anti-angiogenic activity of CN, focusing on the mechanisms of CN inhibition of angiogenesis. CN inhibited migration and invasion, and significantly altered Matrigel-induced tube formation of human umbilical vein endothelial cells (HUVEC), but did not affect cell viability, or MMP-2 and MMP-9 activity. Immunocytochemistry of HUVEC revealed that CN disrupted actin cytoskeleton and altered VE-cadherin distribution at cell-cell contacts. CN downregulated focal adhesion kinase (FAK) and paxillin tyrosine phosphorylation in adherent HUVEC. There was also significant inhibition of angiogenesis in vivo by CN as assessed by implanting Matrigel plugs in C57 mice and measuring ingrowth of blood vessels using either factor VIII staining or hemoglobin determination. In conclusion, the present findings confirm our earlier studies and demonstrate conclusively that CN possess strong anti-angiogenic activity in vitro and in vivo.
Golubkov
Vladislav
V
Department of Biochemistry, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA.
Hawes
Debra
D
Markland
Francis S
FS
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003435:Crotalid Venoms / Q000737:chemistry*; D003599:Cytoskeleton / Q000187:drug effects; D019483:Disintegrins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D008666:Metalloendopeptidases; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D000099152:Cadherin 5
D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D015820:Cadherins; D003435:Crotalid Venoms; D019483:Disintegrins; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D008666:Metalloendopeptidases; D011505:Protein-Tyrosine Kinases; D000099152:Cadherin 5; C031442:Agkistrodon venoms; C403494:contortrostatin; C496050:PTK2 protein, human