a Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham , Edgbaston , Birmingham , UK.
b Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading , Whiteknights , Reading , UK.
Platelets. 2018 Nov;29(7):716-722. doi: 10.1080/09537104.2017.1356919. Epub 2017 Nov 1.
The podoplanin-CLEC-2 axis is critical in mice for prevention of hemorrhage in the cerebral vasculature during mid-gestation. This raises the question as to how platelets are captured by podoplanin on neuroepithelial cells in a high shear environment. In this study, we demonstrate that mouse platelets form stable aggregates on mouse podoplanin at arterial shear through a CLEC-2 and Src kinase-dependent pathway. Adhesion and aggregation are also dependent on the platelet glycoprotein (GP) receptors, integrin αIIbβ3 and GPIb, and the feedback agonists ADP and thromboxane A (TxA). CLEC-2 does not bind to von Willebrand factor (VWF) suggesting that the interaction with podoplanin is sufficient to both tether and activate platelets. Consistent with this, the surface plasmon resonance measurements reveal that mouse CLEC-2 binds to mouse podoplanin with nanomolar affinity. The present findings demonstrate a novel pathway of hemostasis in which podoplanin supports platelet capture and activation at arteriolar rates of shear.
在妊娠中期，足细胞蛋白聚糖-CLEC-2 轴在预防脑血管出血中起着至关重要的作用。这就提出了一个问题，即在高切变环境下，血小板如何被足细胞蛋白聚糖捕获到神经上皮细胞上。在这项研究中，我们证明了通过 CLEC-2 和Src 激酶依赖性途径，在动脉剪切力下，小鼠血小板可以在小鼠足细胞蛋白聚糖上形成稳定的聚集物。黏附和聚集也依赖于血小板糖蛋白（GP）受体整合素 αIIbβ3 和 GPIb，以及反馈激动剂 ADP 和血栓烷 A（TxA）。CLEC-2 不与血管性血友病因子（VWF）结合，这表明与足细胞蛋白聚糖的相互作用足以固定和激活血小板。与此一致的是，表面等离子体共振测量表明，小鼠 CLEC-2 与小鼠足细胞蛋白聚糖的结合具有纳摩尔亲和力。这些发现表明，在足细胞蛋白聚糖支持下，血小板在动脉剪切速率下的捕获和激活形成了一种新的止血途径。
