Role of murine integrin alpha2beta1 in thrombus stabilization and embolization: contribution of thromboxane A2.
Platelets stably interact with collagen via glycoprotein (GP)VI and alpha2beta1integrin. With alpha2-null mice, we investigated the role of alpha2beta1 in thrombus formation and stability in vivo and in vitro. Using a FeCl(3)-induced thrombosis model, in arteries from alpha2-null mice smaller thrombi were formed with more embolization compared to vessels from wild-type mice. Aspirin treatment of wild-type mice causes similar effects, while the thromboxane A(2) analogue U46619 was borderline effective in suppressing the embolisation in alpha2-null mice. In vitro, perfusion of alpha2-null blood over collagen resulted in formation of thrombi that were smaller and looser in appearance, regardless of the presence or absence of coagulation. Aspirin treatment or blockage of thromboxane receptors provoked embolus formation in wildtype blood, while U46619 normalized thrombus formation in blood from alpha2-null mice. We conclude that integrin alpha2beta1 plays a role in stabilizing murine thrombi, likely by enhancing GPVI activation and thromboxane A(2) release. The increased embolization in alpha2-null mice may argue against the use of alpha2beta1 integrin inhibitors for antithrombotic therapy.
Kuijpers
Marijke J E
MJ
Department of Biochemistry, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands. Marijke.Kuijpers@bioch.unimaas.nl
Pozgajova
Miroslava
M
Cosemans
Judith M E M
JM
Munnix
Imke C A
IC
Eckes
Beate
B
Nieswandt
Bernhard
B
Heemskerk
Johan W M
JW
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002712:Chlorides; D003094:Collagen / Q000494:pharmacology; D005290:Ferric Compounds; D038982:Integrin alpha2beta1 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D013923:Thromboembolism / Q000209:etiology; D013927:Thrombosis / Q000139:chemically induced / Q000209:etiology*; D013928:Thromboxane A2 / Q000502:physiology*
D002712:Chlorides; D005290:Ferric Compounds; D038982:Integrin alpha2beta1; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; D001241:Aspirin; C024555:ferric chloride