Thrombospondin-1 promotes hemostasis through modulation of cAMP signaling in blood platelets.
Thrombospondin-1 promotes hemostasis through modulation of cAMP signaling in blood platelets.
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DOI：
10.1182/blood.2020005382
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发表时间：
2021-02-04
期刊：
影响因子：
20.3
通讯作者：
Naseem, Khalid M
中科院分区：
文献类型：
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作者：
Aburima, Ahmed;Berger, Martin;Naseem, Khalid M
血小板反应蛋白-1（TSP-1）在活化时由血小板释放，可增加血小板活化，但其在体内止血中的作用尚不清楚。我们发现TSP-1是一种重要的止血介质，通过调节抑制性环磷酸腺苷（cAMP）信号传导促进血小板活化。TSP-1基因缺失在体外不影响血小板活化，但在体内止血和血栓形成模型显示，TSP-1缺陷小鼠出血时间延长，血栓形成缺陷，并增加对前列环素模拟物伊洛前列素的敏感性。连续转移野生型（WT）而不是TSP-1-/-血小板改善血栓形成表型，表明血小板衍生的TSP-1的关键作用。在功能测定中，TSP-1缺陷型血小板显示出对cAMP信号传导的敏感性增加，血小板聚集的抑制，以及前列环素（PGI 2）的流动下阻滞。血浆交换实验表明，血浆TSP-1不能纠正TSP-1-/-血小板中的PGI 2超敏反应。相比之下，TSP-1-/-血小板与来自WT血小板或纯化TSP-1的释放物孵育，但不与来自TSP-1-/-血小板的释放物孵育，降低了PGI 2的抑制作用。WT血小板的活化导致cAMP积累和下游信号传导减少，这与cAMP水解酶磷酸二酯酶3A（PDE 3A）的活性增加有关。TSP-1-/-小鼠血小板中的PDE 3A活性和cAMP蓄积未受影响。CD 36（TSP-1受体）缺陷的血小板对PGI 2/cAMP信号的敏感性增加，PDE 3A活性降低，而血小板衍生或纯化的TSP-1不影响PDE 3A活性。这种情况表明TSP-1的释放通过调节血管损伤部位的血小板cAMP信号传导来调节体内止血。
Thrombospondin-1 (TSP-1) is released by platelets upon activation and can increase platelet activation, but its role in hemostasis in vivo is unclear. We show that TSP-1 is a critical mediator of hemostasis that promotes platelet activation by modulating inhibitory cyclic adenosine monophosphate (cAMP) signaling. Genetic deletion of TSP-1 did not affect platelet activation in vitro, but in vivo models of hemostasis and thrombosis showed that TSP-1-deficient mice had prolonged bleeding, defective thrombosis, and increased sensitivity to the prostacyclin mimetic iloprost. Adoptive transfer of wild-type (WT) but not TSP-1-/- platelets ameliorated the thrombotic phenotype, suggesting a key role for platelet-derived TSP-1. In functional assays, TSP-1-deficient platelets showed an increased sensitivity to cAMP signaling, inhibition of platelet aggregation, and arrest under flow by prostacyclin (PGI2). Plasma swap experiments showed that plasma TSP-1 did not correct PGI2 hypersensitivity in TSP-1-/- platelets. By contrast, incubation of TSP-1-/- platelets with releasates from WT platelets or purified TSP-1, but not releasates from TSP-1-/- platelets, reduced the inhibitory effects of PGI2. Activation of WT platelets resulted in diminished cAMP accumulation and downstream signaling, which was associated with increased activity of the cAMP hydrolyzing enzyme phosphodiesterase 3A (PDE3A). PDE3A activity and cAMP accumulation were unaffected in platelets from TSP-1-/- mice. Platelets deficient in CD36, a TSP-1 receptor, showed increased sensitivity to PGI2/cAMP signaling and diminished PDE3A activity, which was unaffected by platelet-derived or purified TSP-1. This scenario suggests that the release of TSP-1 regulates hemostasis in vivo through modulation of platelet cAMP signaling at sites of vascular injury.