Thrombin promotes angiogenesis by a mechanism independent of fibrin formation.
The role of thrombin in angiogenesis was investigated in the chick chorioallantoic membrane (CAM) system. alpha-Thrombin promoted angiogenesis in a dose-dependent fashion and at 8.4 pmol/disk reached a maximum of 78% above the control. At a higher dose of alpha-thrombin (25 pmol/disk) the angiogenic effect declines and this can be explained by desensitization of the thrombin receptor. The promotion of angiogenesis by alpha-thrombin is specific as evidenced by the reversal of this effect by hirudin, which binds both the catalytic and the anion-binding exosite of thrombin or by heparin, which binds thrombin and accelerates its inactivation by antithrombin III. gamma-Thrombin, which is catalytically active but lacks the anion-binding exosite required for clotting activity, promotes angiogenesis in the CAM in the same fashion and to the same extent as alpha-thrombin, at doses up to 130 pmol/disk. Phenylalanyl-propyl-arginine chloromethyl ketone (P-PACK)-thrombin, the catalytically inactive analogue of alpha-thrombin that retains the anion-binding exosite, had no significant effect on angiogenesis in the CAM. When combined with alpha-thrombin, P-PACK-thrombin abolished the angiogenesis-promoting effect of alpha-thrombin. These results suggest that alpha-thrombin can promote angiogenesis in the CAM through interaction with its catalytic site without the requirement for fibrin formation.
Tsopanoglou
N E
NE
Department of Pharmacology, University of Patras Medical School, Greece.
Pipili-Synetos
E
E
Maragoudakis
M E
ME
D000481:Allantoin; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology; D002642:Chick Embryo; D002823:Chorion; D003094:Collagen / Q000096:biosynthesis; D005337:Fibrin / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D013917:Thrombin / Q000494:pharmacology*
D000590:Amino Acid Chloromethyl Ketones; D000991:Antithrombins; D000481:Allantoin; D005337:Fibrin; D003094:Collagen; D013917:Thrombin; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone