Loss of matrix metalloproteinase 2 in platelets reduces arterial thrombosis in vivo.
Platelet activation at a site of vascular injury is essential for the arrest of bleeding; however, excessive platelet activation at a site of arterial damage can result in the unwarranted formation of arterial thrombi, precipitating acute myocardial infarction, or ischemic stroke. Activation of platelets beyond the purpose of hemostasis may occur when substances facilitating thrombus growth and stability accumulate. Human platelets contain matrix metalloproteinase 2 (MMP-2) and release it upon activation. Active MMP-2 amplifies the platelet aggregation response to several agonists by potentiating phosphatidylinositol 3-kinase activation. Using several in vivo thrombosis models, we show that the inactivation of the MMP-2 gene prevented thrombosis induced by weak, but not strong, stimuli in mice but produced only a moderate prolongation of the bleeding time. Moreover, using cross-transfusion experiments and wild-type/MMP-2(-/-) chimeric mice, we show that it is platelet-derived MMP-2 that facilitates thrombus formation. Finally, we show that platelets activated by a mild vascular damage induce thrombus formation at a downstream arterial injury site by releasing MMP-2. Thus, platelet-derived MMP-2 plays a crucial role in thrombus formation by amplifying the response of platelets to weak activating stimuli. These findings open new possibilities for the prevention of thrombosis by the development of MMP-2 inhibitors.
Momi
Stefania
S
Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia 06100, Italy.
Falcinelli
Emanuela
E
Giannini
Silvia
S
Ruggeri
Loredana
L
Cecchetti
Luca
L
Corazzi
Teresa
T
Libert
Claude
C
Gresele
Paolo
P
D000818:Animals; D001158:Arteries / Q000201:enzymology* / Q000473:pathology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D003094:Collagen / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015539:Platelet Activation / Q000187:drug effects; D010979:Platelet Function Tests; D013927:Thrombosis / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology
D003094:Collagen; D020778:Matrix Metalloproteinase 2; D004837:Epinephrine