Principal role of glycoprotein VI in α2β1 and αIIbβ3 activation during collagen-induced thrombus formation

被引:83
作者
Lecut, C
Schoolmeester, A
Kuijpers, MJE
Broers, JLV
van Zandvoort, MAMJ
Vanhoorelbeke, K
Deckmyn, H
Jandrot-Perrus, M
Heemskerk, JWM
机构
[1] Maastricht Univ, CARIM, Dept Biochem, NL-6200 MD Maastricht, Netherlands
[2] Maastricht Univ, CARIM, Dept Mol Genet & Cell Biol, NL-6200 MD Maastricht, Netherlands
[3] Maastricht Univ, CARIM, Dept Biophys, NL-6200 MD Maastricht, Netherlands
[4] Katholieke Univ Leuven, Lab Thrombosis Res, Louvain, Belgium
[5] Univ Paris, Fac Xavier Bichat, INSERM, E348, Paris, France
关键词
ADP; collagen; glycoprotein VI; integrins; platelets; thrombus;
D O I
10.1161/01.ATV.0000137974.85068.93
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective-High-shear perfusion of blood over collagen results in rapid platelet adhesion, aggregation, and procoagulant activity. We studied regulation of alpha2beta1 and alphaIIbbeta3 integrin activation during thrombus formation on collagen. Methods and Results-Blockade of glycoprotein (GP) VI by 9O12 antibody or of P2Y purinergic receptors permitted platelet adhesion but reduced aggregate formation, fibrinogen binding, and activation of alpha2beta1 and alphaIIbbeta3, as detected with antibodies IAC-1 and PAC1 directed against activation-dependent epitopes of these integrins. Combined blockade of GPVI and P2Y receptors and thromboxane formation abolished integrin activation but still allowed adhesion of morphologically unstimulated, nonprocoagulant platelets. Exogenous ADP partly restored the suppressive effect of GPVI blockade on integrin alpha2beta1 and alphaIIbbeta3 activation. Adhesion was fully inhibited only with simultaneous blocking of GPVI and alpha2beta1, indicating that the integrin can support platelet-collagen binding in the absence of its activation. Blockade or absence of GPIbalpha only moderately influenced integrin activation and adhesion unless GPVI was inhibited. Conclusions-GPVI- and autocrine-released ADP induce affinity changes of alpha2beta1 and alphaIIbbeta3 during thrombus formation on collagen under flow. These integrin changes are dispensable for adhesion but strengthen platelet-collagen interactions and thereby collagen-induced platelet activation.
引用
收藏
页码:1727 / 1733
页数:7
相关论文
共 35 条
[11]   Collagen but not fibrinogen surfaces induce bleb formation, exposure of phosphatidylserine, and procoagulant activity of adherent platelets: Evidence for regulation by protein tyrosine kinase-dependent Ca2+ responses [J].
Heemskerk, JWM ;
Vuist, WMJ ;
Feijge, MAH ;
Reutelingsperger, CPM ;
Lindhout, T .
BLOOD, 1997, 90 (07) :2615-2625
[12]   Integrin α2β1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLC-γ2 [J].
Inoue, O ;
Suzuki-Inoue, K ;
Dean, WL ;
Frampton, J ;
Watson, SP .
JOURNAL OF CELL BIOLOGY, 2003, 160 (05) :769-780
[13]   Platelet collagen receptor integrin α2β1 activation involves differential participation of ADP-receptor subtypes P2Y1 and P2Y12 but not intracellular calcium change [J].
Jung, SM ;
Moroi, M .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (12) :3513-3522
[14]   Lateral clustering of platelet GP Ib-IX complexes leads to up-regulation of the adhesive function of integrin αIIbβ3 [J].
Kasirer-Friede, A ;
Ware, J ;
Leng, LJ ;
Marchese, P ;
Ruggeri, ZM ;
Stattil, SJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (14) :11949-11956
[15]   The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion [J].
Kato, K ;
Kanaji, T ;
Russell, S ;
Kunicki, TJ ;
Furihata, K ;
Kanaji, S ;
Marchese, P ;
Reininger, A ;
Ruggeri, ZM ;
Ware, J .
BLOOD, 2003, 102 (05) :1701-1707
[16]   Complementary roles of platelet glycoprotein VI and integrin α2β1 in collagen-induced thrombus formation in flowing whole blood ex vivo [J].
Kuijpers, MJE ;
Schulte, V ;
Bergmeier, W ;
Lindhout, T ;
Brakebusch, C ;
Offermanns, S ;
Fässler, R ;
Heemskerk, JWM ;
Nieswandt, B .
FASEB JOURNAL, 2003, 17 (02) :685-+
[17]   Human platelet glycoprotein VI function is antagonized by monoclonal anti body-derived Fab fragments [J].
Lecut, C ;
Feeney, LA ;
Kingsbury, G ;
Hopkins, J ;
Lanza, F ;
Gachet, C ;
Villeval, JL ;
Jandrot-Perrus, M .
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2003, 1 (12) :2653-2662
[18]   A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo [J].
Massberg, S ;
Gawaz, M ;
Grüner, S ;
Schulte, V ;
Konrad, I ;
Zohlnhöfer, D ;
Heinzmann, U ;
Nieswandt, B .
JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 197 (01) :41-49
[19]  
Moroi M, 1997, THROMB HAEMOSTASIS, V78, P439
[20]   Glycoprotein VI but not α2β1 integrin is essential for platelet interaction with collagen [J].
Nieswandt, B ;
Brakebusch, C ;
Bergmeier, W ;
Schulte, V ;
Bouvard, D ;
Mokhtari-Nejad, R ;
Lindhout, T ;
Heemskerk, JWM ;
Zirngibl, H ;
Fässler, R .
EMBO JOURNAL, 2001, 20 (09) :2120-2130