Intercellular calcium communication regulates platelet aggregation and thrombus growth

Nesbitt, Warwick Scott; Giuliano, Simon; Kulkarni, Suhasini; Dopheide, Sacha M; Harper, Ian S.; Jackson, Shaun P.

doi:10.1083/jcb.200207119

Cited by 164 publications

(144 citation statements)

References 58 publications

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“…Indeed, thrombus formation in the outlet region was eliminated in the presence of cyclooxygenase inhibition and ADP receptor blockade. The high shear stress in the stenosis apex may trigger release of thromboxane A 2 and ADP, which are known to contribute to aggregate formation at high shear stress (28,29), whereas the immediate reduction in shear stress load in the outlet region favors autocrine agonistdependent platelet aggregation. The stenotic geometry couples high shear stress-induced release of autocrine agonists with a region of low shear stress.…”

Section: Discussionmentioning

confidence: 99%

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

Westein

Meer

Kuijpers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

245

257

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Rupture of a vulnerable atherosclerotic plaque causes thrombus formation and precipitates cardiovascular diseases. In addition to the thrombogenic content of a plaque, also the hemodynamic microenvironment plays a major role in thrombus formation. How the altered hemodynamics around a plaque promote pathological thrombus formation is not well understood. In this study, we provide evidence that plaque geometries result in fluid mechanical conditions that promote platelet aggregation and thrombus formation by increased accumulation and activity of von Willebrand factor (vWF) at poststenotic sites. Resonant-scanning multiphoton microscopy revealed that in vivo arterial stenosis of a damaged carotid artery markedly increased platelet aggregate formation in the stenotic outlet region. Complementary in vitro studies using microfluidic stenotic chambers, designed to mimic the flow conditions in a stenotic artery, showed enhanced platelet aggregation in the stenotic outlet region at 60-80% channel occlusion over a range of input wall shear rates. The poststenotic thrombus formation was critically dependent on bloodborne vWF and autocrine platelet stimulation. In stenotic chambers containing endothelial cells, flow provoked increased endothelial vWF secretion in the stenotic outlet region, contributing to exacerbated platelet aggregation. Taken together, this study identifies a role for the shear-sensitive protein vWF in transducing hemodynamic forces that are present around a stenosis to a prothrombogenic microenvironment resulting in spatially confined and exacerbated platelet aggregation in the stenosis outlet region. The developed stenotic microfluidic chamber offers a realistic platform for in vitro evaluation of shear-dependent thrombus formation in the setting of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

Westein

Meer

Kuijpers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

245

257

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“…The Ca 2ϩ dye-loaded platelets were treated with c7E3 Fab (20 g/ml) and then allowed to adhere to a vWf (10 M) matrix in the presence of ristocetin (1 mg/ml), under static conditions. The changes in fluorescence ratio of Oregon Green to Fura Red was then measured after 10 min of adhesion using confocal microscopy (1 frame/s) and converted to intracellular Ca 2ϩ concentrations as previously described (31). The Ca 2ϩ concentrations in resting platelets were also determined by measuring the fluorescence ratio (mean ratio ϭ 0.6, n ϭ 390) in platelets applied onto a non-reactive (10% human serum-coated) surface.…”

Section: Methodsmentioning

confidence: 99%

Signaling Role for Phospholipase Cγ2 in Platelet Glycoprotein Ibα Calcium Flux and Cytoskeletal Reorganization

Mangin

Yao

Goncalves

et al. 2003

Journal of Biological Chemistry

Self Cite

105

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Interaction of the platelet GPIb-V-IX complex with surface immobilized von Willebrand factor (vWf) is required for the capture of circulating platelets and their ensuing activation. In previous work, it was found that GPIb/vWf-mediated platelet adhesion triggers Ca 2؉ release from intracellular stores, leading to cytoskeletal reorganization and filopodia extension. Despite the potential functional importance of GPIb-induced cytoskeletal changes, the signaling mechanisms regulating this process have remained ill-defined. The studies presented here demonstrate an important role for phospholipase C (PLC)-dependent phosphoinositide turnover for GPIb-dependent cytoskeletal remodeling. This is supported by the findings that the vWf-GPIb interaction induced a small increase in inositol 1,4,5-triphosphate (IP 3 ) and that treating platelets with the IP 3 receptor antagonist APB-2 or the PLC inhibitor U73122 blocked cytosolic Ca 2؉ flux and platelet shape change. Normal shape change was observed in G␣ q ؊/؊ mouse platelets, excluding a role for PLC␤ isoforms in this process. However, decreased shape change and Ca 2؉ mobilization were observed in mice lacking PLC␥2, demonstrating that this isotype played an important, albeit incomplete, role in GPIb signaling. The signaling pathways utilized by GPIb involved one or more members of the Src kinase family as platelet shape change and Ca 2؉ flux were inhibited by the Src kinase inhibitors PP1 and PP2. Strikingly, shape change and Ca 2؉ release occurred independently of immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, because these platelet responses were normal in human platelets treated with the anti-Fc␥RIIA blocking monoclonal antibody IV.3 and in mouse platelets deficient in the FcR␥ chain. Taken together, these studies define an important role for PLC␥2 in GPIb signaling linked to platelet shape change. Moreover, they demonstrate that GPIb-dependent calcium flux and cytoskeletal reorganization involves a signaling pathway distinct from that utilized by ITAM-containing receptors.

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“…Physiological plasma calcium concentration is among the most important factors for normal platelet aggregation. Coordination of calcium flux through plateletplatelet contact serves to propagate calcium signaling throughout the developing thrombus to maintain thrombus growth (19). Thus, it is plausible to assume that the impaired platelet aggregation in hypocalcemic VDRKO mice was caused by the hypocalcemia in these mice.…”

Section: Figmentioning

confidence: 99%

Disruption of Nuclear Vitamin D Receptor Gene Causes Enhanced Thrombogenicity in Mice

Aihara¹,

Azuma²,

Akiyama³

et al. 2004

Journal of Biological Chemistry

236

161

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Vitamin D metabolites influence the expression of various genes involved in calcium homeostasis, cell differentiation, and regulation of the immune system. Expression of these genes is mediated by the activation of the nuclear vitamin D receptor (VDR). Previous studies have shown that a hormonally active form of vitamin D, 1␣,25-dihydroxyvitamin D3, exerts anticoagulant effects in cultured monocytic cells. To clarify whether activation of VDR plays any antithrombotic actions in vivo, hemostatic/thrombogenic systems were examined in normocalcemic VDR knock-out (KO) mice on a high calcium diet and compared with wild type and hypocalcemic VDRKO mice that were fed a regular diet. Platelet aggregation was enhanced significantly in normocalcemic VDRKO mice compared with wild type and hypocalcemic VDRKO mice. Aortic endothelial nitric-oxide (NO) synthase expression and urinary NOx excretions were reduced in hypocalcemic VDRKO mice, but not in normocalcemic VDRKO mice. Northern blot and RT-PCR analyses revealed that the gene expression of antithrombin in the liver as well as that of thrombomodulin in the aorta, liver and kidney was down-regulated in hypo-and normocalcemic VDRKO mice. Whereas tissue factor mRNA expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ thrombus formation after exogenous lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that activation of nuclear VDR elicits antithrombotic effects in vivo, and suggest that the VDR system may play a physiological role in the maintenance of antithrombotic homeostasis.

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Intercellular calcium communication regulates platelet aggregation and thrombus growth

Cited by 164 publications

References 58 publications

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

Signaling Role for Phospholipase Cγ2 in Platelet Glycoprotein Ibα Calcium Flux and Cytoskeletal Reorganization

Disruption of Nuclear Vitamin D Receptor Gene Causes Enhanced Thrombogenicity in Mice

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