Service and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, rue du Bugnon 46, CH-1011 Lausanne, Switzerland.
Circulation. 2011 Aug 23;124(8):930-9. doi: 10.1161/CIRCULATIONAHA.110.015479. Epub 2011 Aug 1.
Formation of platelet plug initiates hemostasis after vascular injury and triggers thrombosis in ischemic disease. However, the mechanisms leading to the formation of a stable thrombus are poorly understood. Connexins comprise a family of proteins that form gap junctions enabling intercellular coordination of tissue activity, a process termed gap junctional intercellular communication.
In the present study, we show that megakaryocytes and platelets express connexin 37 (Cx37). Deletion of the Cx37 gene in mice shortens bleeding time and increases thrombus propensity. Aggregation is increased in murine Cx37(-/-) platelets or in murine Cx37(+/+) and human platelets treated with gap junction blockers. Intracellular microinjection of neurobiotin, a Cx37-permeant tracer, revealed gap junctional intercellular communication in platelet aggregates, which was impaired in Cx37(-/-) platelets and in human platelets exposed to gap junction blockers. Finally, healthy subjects homozygous for Cx37-1019C, a prognostic marker for atherosclerosis, display increased platelet responses compared with subjects carrying the Cx37-1019T allele. Expression of these polymorphic channels in communication-deficient cells revealed a decreased permeability of Cx37-1019C channels for neurobiotin.
We propose that the establishment of gap junctional communication between Cx37-expressing platelets provides a mechanism to limit thrombus propensity. To our knowledge, these data provide the first evidence incriminating gap junctions in the pathogenesis of thrombosis.
血小板栓子的形成启动了血管损伤后的止血，并在缺血性疾病中引发血栓形成。然而，导致稳定血栓形成的机制还知之甚少。连接蛋白构成了一组蛋白质，它们形成间隙连接，使组织活动在细胞间协调，这个过程称为间隙连接细胞间通讯。
在本研究中，我们表明巨核细胞和血小板表达连接蛋白 37（Cx37）。在小鼠中敲除 Cx37 基因会缩短出血时间并增加血栓形成倾向。在缺乏 Cx37 的小鼠血小板或用间隙连接阻断剂处理的小鼠 Cx37(+/+)和人血小板中，聚集增加。细胞内微注射神经生物素，一种 Cx37 可渗透的示踪剂，显示血小板聚集中有间隙连接细胞间通讯，在缺乏 Cx37 的血小板和暴露于间隙连接阻断剂的人血小板中，这种通讯受损。最后，载有动脉粥样硬化预后标志物 Cx37-1019C 的健康受试者的血小板反应高于携带 Cx37-1019T 等位基因的受试者。在通讯缺陷细胞中表达这些多态性通道显示 Cx37-1019C 通道对神经生物素的通透性降低。
我们提出，表达 Cx37 的血小板之间建立间隙连接通讯提供了一种限制血栓形成倾向的机制。据我们所知，这些数据首次提供了证据表明间隙连接参与了血栓形成的发病机制。
