Abstract
The platelet receptor CLEC-2 is involved in thrombosis/hemostasis, but its ligand, podoplanin, is expressed only in advanced atherosclerotic lesions. We investigated CLEC-2 ligands in vessel walls. Recombinant CLEC-2 bound to early atherosclerotic lesions and normal arterial walls, co-localizing with vascular smooth muscle cells (VSMCs). Flow cytometry and immunocytochemistry showed that recombinant CLEC-2, but not an anti-podoplanin antibody, bound to VSMCs, suggesting that CLEC-2 ligands other than podoplanin are present in VSMCs. VSMCs stimulated platelet granule release and supported thrombus formation under flow, dependent on CLEC-2. The time to occlusion in a FeCl3-induced animal thrombosis model was significantly prolonged in the absence of CLEC-2. Because the internal elastic lamina was lacerated in our FeCl3-induced model, we assume that the interaction between CLEC-2 and its ligands in VSMCs induces thrombus formation. Protein arrays and Biacore analysis were used to identify S100A13 as a CLEC-2 ligand in VSMCs. However, S100A13 is not responsible for the above-described VSMC-induced platelet activation, because S100A13 is not expressed on the surface of normal VSMCs. S100A13 was released upon oxidative stress and expressed in the luminal area of atherosclerotic lesions. Suspended S100A13 did not activate platelets, but immobilized S100A13 significantly increased thrombus formation on collagen-coated surfaces. Taken together, we proposed that VSMCs stimulate platelets through CLEC-2, possibly leading to thrombus formation after plaque erosion and stent implantation, where VSMCs are exposed to blood flow. Furthermore, we identified S100A13 as one of the ligands on VSMCs.
Highlights
CLEC-2 has been identified as a receptor for the platelet-activating snake venom rhodocytin/ aggretin[1]
CLEC-2 ligands other than podoplanin are expressed on the surface of vascular smooth muscle cells (VSMCs) and that association between CLEC-2 and the ligand activates platelets and facilitates thrombus formation under flow conditions
We propose that CLEC-2 ligands other than podoplanin are expressed on the surface of both normal and pathologic VSMCs and contribute to thrombus formation through CLEC-2 in vivo and in vitro
Summary
CLEC-2 has been identified as a receptor for the platelet-activating snake venom rhodocytin/ aggretin[1]. It elicits robust platelet aggregation through a tyrosine kinase-depending signaling pathway[1]. We identified podoplanin as an endogenous ligand for CLEC-2 for the first time [2]. Podoplanin is expressed on the surface of tumor cells and induces platelet aggregation by binding to CLEC-2, facilitating hematogenous tumor metastasis[2, 3]. It is expressed in lymphatic endothelial cells, but not in vascular endothelial cells[4]. CLEC-2-deficient mice show embryonic/neonatal lethality and blood-filled lymphatic vessels[5,6,7], suggesting that CLEC-2 facilitates blood/lymphatic vessel separation by interacting with podoplanin in lymphatic endothelial cells[8, 9]
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