On the mechanism(s) of thrombin induced angiogenesis.
Promotion of tumour progression by thrombin is suggested by several clinical and laboratory observations. A plausible explanation for this effect of thrombin may be related to our previous findings that thrombin is a potent promoter of angiogenesis in the chick chorioallantoic membrane system (CAM) and in the Matrigel system in vivo. In this report we summarise the cellular and molecular actions of thrombin that could be contributing to the activation of angiogenic cascade. Treatment of endothelial cells with thrombin leads to activation of gelatinase A, which may allow for local dissolution of basement membrane, an essential first step of angiogenesis. Similarly thrombin-treated endothelial cells have diminished ability to adhere to collagen type IV and laminin. This new phenotype of endothelial cells can migrate and survive without attachment to extracellular matrix. Thrombin-treatment of endothelial cells increases the vectorial secretion of extracellular matrix proteins, a process essential at the final steps of angiogenesis. In addition, thrombin potentiates the VEGF-induced mitogenesis of endothelial cells. This can be explained by the upregulation of the VEGF receptors (KDR & flt-1) by thrombin treatment. All the aforementioned effects of thrombin are receptor mediated, dose-dependent and require only brief exposure of endothelial cells to thrombin for these actions of thrombin. The transduction mechanisms involved are via protein kinase C (PKC) and MAP-kinase pathways.
Maragoudakis
M E
ME
University of Patras Medical School, Department of Pharmacology, Greece.
Tsopanoglou
N E
NE
D000818:Animals; D001672:Biocompatible Materials; D002645:Chickens; D002823:Chorion; D003094:Collagen; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004792:Enzyme Precursors / Q000378:metabolism; D005109:Extracellular Matrix; D018093:Gelatinases / Q000378:metabolism; D007797:Laminin; D008222:Lymphokines / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011509:Proteoglycans; D013917:Thrombin / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D001672:Biocompatible Materials; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D004792:Enzyme Precursors; D007797:Laminin; D008222:Lymphokines; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; D003094:Collagen; D013917:Thrombin; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase