Complementary roles of platelet glycoprotein VI and integrin α2β1 in collagen-induced thrombus formation in flowing whole blood ex vivo

被引:121
作者
Kuijpers, MJE
Schulte, V
Bergmeier, W
Lindhout, T
Brakebusch, C
Offermanns, S
Fässler, R
Heemskerk, JWM
Nieswandt, B
机构
[1] Univ Maastricht, CARIM, Dept Biochem & Human Biol, NL-6200 MD Maastricht, Netherlands
[2] Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, D-97078 Wurzburg, Germany
[3] Max Planck Inst Biochem, Dept Mol Med, D-82152 Martinsried, Germany
[4] Heidelberg Univ, Dept Pharmacol, D-69120 Heidelberg, Germany
关键词
collagen receptors; flow model; phosphatidylserine; platelet aggregation; whole blood perfusion;
D O I
10.1096/fj.02-0381fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Platelets interact vigorously with subendothelial collagens that are exposed by injury or pathological damage of a vessel wall. The collagen-bound platelets trap other platelets to form aggregates, and they expose phosphatidylserine (PS) required for coagulation. Both processes are implicated in the formation of vaso-occlusive thrombi. We previously demonstrated that the immunoglobulin receptor glycoprotein VI (GPVI), but not integrin alpha2beta1, is essential in priming platelet-collagen interaction and subsequent aggregation. Here, we report that these receptors have yet a complementary function in ex vivo thrombus formation during perfusion of whole blood over collagen. With mice deficient in GPVI or blocking antibodies, we found that GPVI was indispensable for collagen-dependent Ca2+ mobilization, exposure of PS, and aggregation of platelets. Deficiency of integrin beta1 reduces the GPVI-evoked responses but still allows the formation of loose platelet aggregates. By using mice deficient in Galpha(q) or specific thromboxane A(2) and ADP antagonists, we show that these autocrine agents mediated aggregation but not collagen-induced Ca2+ mobilization or PS exposure. Collectively, these data indicate that integrin alpha2beta1 facilitates the central function of GPVI in the platelet activation processes that lead to thrombus formation, whereas the autocrine thromboxane A(2) and ADP serve mainly to trigger aggregate formation.
引用
收藏
页码:685 / +
页数:23
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