Vascular Smooth Muscle Cells Stimulate Platelets and Facilitate Thrombus Formation through Platelet CLEC-2: Implications in Atherothrombosis

Ito, Osamu; Hokamura, Kazuya; Shirai, Toshiaki; Osada, Makoto; Tsukiji, Nagaharu; Hatakeyama, Kinta; Umemura, Kazuo; Asada, Yujiro; Suzuki‐Inoue, Katsue; Ozaki, Yukio

doi:10.1371/journal.pone.0139357

Cited by 52 publications

(57 citation statements)

References 41 publications

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“…Moreover, Min Fei found that the plasma level of CLEC-2 was positively correlated with the plasma GPVI level [11]. C-type lectin-like receptor 2 was found in atherosclerotic lesions, especially in advanced atherosclerotic lesions, indicating the role of CLEC-2 in atherosclerotic lesion formation [9,10]. Atherosclerotic lesion formation is the main cause of atherosclerotic diseases.…”

Section: Discussionmentioning

confidence: 99%

Plasma C‐type lectin‐like receptor 2 as a predictor of death and vascular events in patients with acute ischemic stroke

Zhang

et al. 2019

Euro J of Neurology

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Background and purpose C‐type lectin‐like receptor 2 (CLEC‐2) has prominent involvement in platelet activation, which is increased in coronary heart disease and acute ischaemic stroke (AIS) and is associated with stroke progression and stroke prognosis. Here, the aim was to examine the prognostic value of CLEC‐2 in death and vascular event recurrence in AIS patients. Methods In all, 352 patients with AIS were studied prospectively. All patients were followed up for 1 year. Death for all vascular events and a combination of death and vascular diseases (recurrent stroke, myocardial infarction, hospitalized and treated angina, hospitalized and treated peripheral arterial disease) were recorded. Results During 1 year of follow‐up, 46 patients (14.2%) experienced death or combined end‐points (23 death and 46 combined end‐points). Plasma CLEC‐2 (pCLEC‐2) was significantly associated with an increased risk of death and combined events of death and vascular diseases after adjusting for age, sex, history of hypertension, diabetes mellitus and coronary artery disease, and National Institutes of Health Stroke Scale scores. Each 1 SD higher log‐transformed pCLEC‐2 was associated with a 4.27‐fold (hazard ratio 4.27, 95% confidence interval 1.71–10.65) increased risk for death and a 2.42‐fold increased risk for combined end‐points (hazard ratio 2.42, 95% confidence interval 1.52–3.86). The optimal cut‐off point of pCLEC‐2 for predicting death was 184.38 pg/ml. Conclusions Higher pCLEC‐2 levels at admission were associated with increased risk of death and combined events of death and vascular diseases in patients with AIS, which indicated that pCLEC‐2 is an important prognostic factor for AIS.

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Section: Discussionmentioning

confidence: 99%

Plasma C‐type lectin‐like receptor 2 as a predictor of death and vascular events in patients with acute ischemic stroke

Zhang

et al. 2019

Euro J of Neurology

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“…CLEC-2-deficient platelets resulting from both methods showed normal adhesion to collagencoated capillaries under flow conditions, but the subsequent thrombus formation was severely impaired in vitro, although platelet aggregation induced by agonists other than rhodocytin was normal [27,39]. FeCl 3 -induced thrombus formation in the artery was also inhibited in CLEC-2deficient chimeras [39,40]. These mice also showed mildly increased or mild but not significantly increased tail bleeding [10,27,39].…”

Section: Thrombus Stability Under Flow Condition (Platelet Clec-2 Andmentioning

confidence: 99%

“…However, Suzuki-Inoue et al proposed platelet activation-dependent hemophilic association of CLEC-2 under flow conditions, based on surface plasmon resonance analysis using recombinant CLEC-2, and flow cytometry analysis using CLEC-2-deficient platelets. Inoue et al showed that S100A13 is a potential CLEC-2 ligand, based on protein array, surface plasmon resonance analysis using recombinant proteins, and an adhesion assay on S100A13-coated surfaces [40]. S100A13 is expressed in the cytoplasm of vascular smooth muscle cells, and is secreted from the cytoplasm upon heat shock, serum depletion, or oxidative stress [40,43,44].…”

Section: Thrombus Stability Under Flow Condition (Platelet Clec-2 Andmentioning

confidence: 99%

“…S100A13 is expressed in the cytoplasm of vascular smooth muscle cells, and is secreted from the cytoplasm upon heat shock, serum depletion, or oxidative stress [40,43,44]. S100A13 is also exposed to blood flow at the site of vascular injury caused by FeCl 3 and atherosclerotic lesions, which may potentiate thrombus formation by it binding to CLEC-2 [40]. Further study on S100A13-deficient mice is required for definite demonstration of an in vivo role of S100A13.…”

Section: Thrombus Stability Under Flow Condition (Platelet Clec-2 Andmentioning

confidence: 99%

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Physiologic and pathophysiologic roles of interaction between C‐type lectin‐like receptor 2 and podoplanin: partners from in utero to adulthood

Suzuki‐Inoue

Osada

Ozaki

2017

Journal of Thrombosis and Haemostasis

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Summary A platelet activation receptor, C‐type lectin‐like receptor 2 (CLEC‐2), has been identified as a receptor for a platelet‐activating snake venom, rhodocytin. CLEC‐2 protein is highly expressed in platelets/megakaryocytes, and at lower levels in liver Kupffer cells. Recently, podoplanin has been revealed as an endogenous ligand for CLEC‐2. Podoplanin is expressed in certain types of tumor cells, fibroblastic reticular cells (FRCs) in lymph nodes, kidney podocytes, and lymphatic endothelial cells, but not in vascular endothelial cells. CLEC‐2 in platelets cannot have access to podoplanin under normal conditions, but they interact with each other under pathologic conditions or during developmental stages, and play various pathophysiologic roles. CLEC‐2 facilitates hematogenous metastasis of podoplanin‐expressing tumors. During development, the interaction between CLEC‐2 and podoplanin in lymphatic endothelial cells or neuroepithelial cells facilitates blood–lymphatic vessel separation and cerebrovascular patterning and integrity, respectively. In adulthood, platelet CLEC‐2 binding to FRCs is crucial for maintenance of the integrity of high endothelial venules in lymph nodes. Podoplanin‐expressing FRC‐like cells have recently been identified in the bone marrow, and facilitate megakaryocyte proliferation and proplatelet formation by binding to megakaryocyte CLEC‐2. Podoplanin is inducibly expressed in liver monocytes and keratinocytes during Salmonella infection and wound healing, and regulates thrombus formation in the liver and controlled wound healing, respectively. By binding to unknown ligands, platelet CLEC‐2 regulates the maintenance of vascular integrity during inflammation, thrombus stability under flow, and maintenance of quiescence of hematopoietic stem cells. Podoplanin is expressed in various cells, and additional roles of the CLEC‐2–podoplanin interaction will be revealed in the future.

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“…The interaction of CLEC-2 with podoplanin, which is exposed on the surface of lymphatic endothelial cells (LECs), is crucial for the separation of blood and lymphatic systems during embryogenesis (Bertozzi et al, 2010;Suzuki-Inoue et al, 2010;Hughes et al, 2015) and for the prevention of blood-lymph mixing in high endothelial venules and lymph nodes in adult organisms (Herzog et al, 2013). Platelet CLEC-2 also contributes to the maintenance of blood vessel integrity during inflammatory conditions (Boulaftali et al, 2013;Hughes et al, 2010a;Bender et al, 2013;Gros et al, 2015;Hughes et al, 2015) and has a role in thrombus stabilization under flow conditions Inoue et al, 2015;Hughes et al, 2010). Participation of platelet CLEC-2 has been demonstrated for a set of pathophysiological processes: promotion of tumor metastasis (Kato et al, 2008;Shirai et al, 2017), liver thrombosis after Salmonella Infection (Hitchcock et al, 2015), purpura and thrombocytopenia during Kazabach-Merritt syndrome in infants (O'Rafferty et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Diffusional and chemical control in the tyrosine kinase network of platelet CLEC-2 signalling

Martyanov

Fa²,

et al. 2019

Preprint

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C-type lectin-like receptor 2 (CLEC-2) is platelet membrane glycoprotein implicated in maintenance of blood vessel integrity and development of lymphatics. Organization and regulation of tyrosine kinase signalling network associated with CLEC-2 is poorly understood. Here we aimed to investigate CLEC-2 signal transduction using computational systems biology methods in combination with experimental approaches.We developed a 3D/stochastic multicompartmental computational model of CLEC-2 signalling, which was built around membrane-associated signalosome formation.The model predicted that both Syk and Src-family kinases phosphorylate CLEC-2, and that CLEC-2 ligation induces cytosolic calcium spiking. This was experimentally confirmed using flow cytometry and TIRF microscopy, respectively. Sensitivity analysis suggested that the CLEC-2 translocation to the signalosome region is one of the rate-limiting steps in the signal transduction process. In agreement with this prediction, CLEC-2-induced platelet activation was strongly temperature-dependent (unlike that mediated by G-protein coupled receptors) and was delayed by lipid raft disruption.Our results suggest a revised picture of the CLEC-2 signal transduction network functioning that emphasizes the crucial role of lipid raft structural rearrangement followed by tyrosine kinase feedback interplay. Keywords: intracellular signalling/platelet receptors/tyrosine kinases/computational modelling AbbreviationsCLEC-2 -C-type lectin-like receptor 2; LEC -lymphatic endothelial cells; GPVI -glycoprotein VI; FcR -Fc receptor; ITAM -immune tyrosine activation motif; Syk -spleen tyrosine kinase; SFK -Src-family kinase; PI3K -phosphoinositide 3-kinase; PIP2 -phosphatidylinositol 4,5-bisphosphate; PIP3phosphatidylinositol 3,4,5-trisphosphate; LAT -linker adapter for T-Cells; PLCɣ2 -phospholipase Cɣ2; PGI2 -prostaglandin I2; mβCD -methyl β cyclodextrin; TIRF -total internal reflection; PTP1B -protein tyrosine phosphatase 1B; Btk -Bruton's tyrosine kinase, TxA2 -Thromboxane A2.

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Vascular Smooth Muscle Cells Stimulate Platelets and Facilitate Thrombus Formation through Platelet CLEC-2: Implications in Atherothrombosis

Cited by 52 publications

References 41 publications

Plasma C‐type lectin‐like receptor 2 as a predictor of death and vascular events in patients with acute ischemic stroke

Plasma C‐type lectin‐like receptor 2 as a predictor of death and vascular events in patients with acute ischemic stroke

Physiologic and pathophysiologic roles of interaction between C‐type lectin‐like receptor 2 and podoplanin: partners from in utero to adulthood

Diffusional and chemical control in the tyrosine kinase network of platelet CLEC-2 signalling

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