Special Article

Li, Jianming; Podolsky, Robert S.; Rohrer, Michael J.; Cutler, Bruce S.; Massie, Mitchell T.; Barnard, Marc R.; Michelson, Alan D.

doi:10.1006/jsre.1996.0161

Cited by 47 publications

(6 citation statements)

References 3 publications

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“…Thus, it seemed very likely that the same mechanism mediated platelet binding to endothelial cells. Indeed, blockade of GPIIbIIIa by the mAb P2 or RGD peptides decreased platelet binding to HUVEC monolayers by ∼50%, which is comparable to a recent report ( 7 ). Although both RGD peptides and the mAb P2 have been shown to block completely platelet aggregation ( 19 ), platelet binding to HUVEC was not inhibited 100% by these antagonists.…”

Section: Discussionsupporting

confidence: 89%

“…So far, three different platelet receptors have been reported to be involved in the binding to endothelium. Rolling of activated platelets on high endothelial venules was found to depend primarily on platelet P-selectin (α IIb β 3 ; CD62P; 6), whereas firm adhesion to human saphenous vein endothelial cells was inhibited by anti-GPIIbIIIa (CD41a/ CD61) antibodies and RGD peptides ( 7 ). Furthermore, it has been shown that platelet-sialylated glycoproteins may, at least in part, be responsible for the increased adhesion of platelets from diabetics to bovine valvular endothelial cells ( 8 ).…”

mentioning

confidence: 99%

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Adhesion of Activated Platelets to Endothelial Cells: Evidence for a GPIIbIIIa-dependent Bridging Mechanism and Novel Roles for Endothelial Intercellular Adhesion Molecule 1 (ICAM-1), αvβ3 Integrin, and GPIbα

Bombeli

Schwartz

Harlan

1998

The Journal of Experimental Medicine

395

269

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Although it has been reported that activated platelets can adhere to intact endothelium, the receptors involved have not been fully characterized. Also, it is not clear whether activated platelets bind primarily to matrix proteins at sites of endothelial cell denudation or directly to endothelial cells. Thus, this study was designed to further clarify the mechanisms of activated platelet adhesion to endothelium. Unstimulated human umbilical vein endothelial cell (HUVEC) monolayers were incubated with washed, stained, and thrombin-activated human platelets. To exclude matrix involvement, HUVEC were harvested mechanically and platelet binding was measured by flow cytometry. Before the adhesion assay, platelets or HUVEC were treated with different receptor antagonists. Whereas blockade of platelet β1 integrins, GPIbα, GPIV, P-selectin, and platelet-endothelial cell adhesion molecule (PECAM)-1 did not reduce platelet adhesion to HUVEC, blockade of platelet GPIIbIIIa by antibodies or Arg-Gly-Asp (RGD) peptides markedly decreased adhesion. Moreover, when platelets were treated with blocking antibodies to GPIIbIIIa-binding adhesive proteins, including fibrinogen and fibronectin, and von Willebrand factor (vWF), platelet binding was also reduced markedly. Addition of fibrinogen, fibronectin, or vWF further increased platelet adhesion, indicating that both endogenous platelet-exposed and exogenous adhesive proteins can participate in the binding process. Evaluation of the HUVEC receptors revealed predominant involvement of intercellular adhesion molecule (ICAM)-1 and αvβ3 integrin. Blockade of these two receptors by antibodies decreased platelet binding significantly. Also, there was evidence that a component of platelet adhesion was mediated by endothelial GPIbα. Blockade of β1 integrins, E-selectin, P-selectin, PECAM-1, vascular cell adhesion molecule (VCAM)-1 and different matrix proteins on HUVEC did not affect platelet adhesion. In conclusion, we show that activated platelet binding to HUVEC monolayers is mediated by a GPIIbIIIa-dependent bridging mechanism involving platelet-bound adhesive proteins and the endothelial cell receptors ICAM-1, αvβ3 integrin, and, to a lesser extent, GPIbα.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Adhesion of Activated Platelets to Endothelial Cells: Evidence for a GPIIbIIIa-dependent Bridging Mechanism and Novel Roles for Endothelial Intercellular Adhesion Molecule 1 (ICAM-1), αvβ3 Integrin, and GPIbα

Bombeli

Schwartz

Harlan

1998

The Journal of Experimental Medicine

395

269

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“…After the initial tethering and rolling steps [ 21 , 23 , 24 , 73 ], arrest and firm adhesion, including spreading of platelets to EC appear to essentially implicate the αIIbβ3 integrin on the platelet side, while several counter-receptors have been identified on activated EC. The latter include the αVβ3 integrin, with bridging of the two integrins by their shared, RGD-type adhesive proteins fibrinogen and/or VWF, as well as intercellular adhesion molecule-1 (ICAM-1) through bridging by fibrinogen [ 22 , 48 , 74 ]. Remarkably, however, the combination of blocking antibodies targeting simultaneously the αVβ3 integrin and ICAM-1 on EC appears to reduce the platelet–EC interaction by no more than 50% [ 22 ], suggesting that other endothelial receptor(s) could be involved in the final step of firm platelet adherence and spreading.…”

Section: Discussionmentioning

confidence: 99%

Human endoglin as a potential new partner involved in platelet–endothelium interactions

Rossi

Pericacho

Bachelot‐Loza

et al. 2017

Cell. Mol. Life Sci.

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Complex interactions between platelets and activated endothelium occur during the thrombo-inflammatory reaction at sites of vascular injuries and during vascular hemostasis. The endothelial receptor endoglin is involved in inflammation through integrin-mediated leukocyte adhesion and transmigration; and heterozygous mutations in the endoglin gene cause hereditary hemorrhagic telangiectasia type 1. This vascular disease is characterized by a bleeding tendency that is postulated to be a consequence of telangiectasia fragility rather than a platelet defect, since platelets display normal functions in vitro in this condition. Here, we hypothesize that endoglin may act as an adhesion molecule involved in the interaction between endothelial cells and platelets through integrin recognition. We find that the extracellular domain of human endoglin promotes specific platelet adhesion under static conditions and confers resistance of adherent platelets to detachment upon exposure to flow. Also, platelets adhere to confluent endothelial cells in an endoglin-mediated process. Remarkably, Chinese hamster ovary cells ectopically expressing the human αIIbβ3 integrin acquire the capacity to adhere to myoblast transfectants expressing human endoglin, whereas platelets from Glanzmann’s thrombasthenia patients lacking the αIIbβ3 integrin are defective for endoglin-dependent adhesion to endothelial cells. Furthermore, the bleeding time, but not the prothrombin time, is significantly prolonged in endoglin-haplodeficient (Eng +/−) mice compared to Eng +/+ animals. These results suggest a new role for endoglin in αIIbβ3 integrin-mediated adhesion of platelets to the endothelium, and may provide a better understanding on the basic cellular mechanisms involved in hemostasis and thrombo-inflammatory events.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-017-2694-7) contains supplementary material, which is available to authorized users.

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“…Third, neutrophil depletion in Kindlin-3 fl/fl LysM-Cre mice suppresses DVT (Figure 2C). In addition, the kindlin-3-αIIbβ3 signaling in platelets plays an important role in promoting both DVT and NET release (Figure 2D) [1, 28, 29]. Nonetheless, the involvement of NETs may not be the sole mechanism in supporting DVT in Kindlin-3 fl/fl LysM-Cre mice due to the fact that deficiency of kindlin-3 can have multiple consequences in neutrophils [25, 30].…”

Section: Discussionmentioning

confidence: 99%

Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice

Yan

Yang

Xiao

et al. 2019

Aging

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Platelets and myeloid cells cooperate to promote deep vein thrombosis (DVT). Here we evaluated the role of kindlin-3, a key integrin activator in these cells, in regulating stenosis-induced DVT in mice. DVT was significantly suppressed in mice that express a kindlin-3 mutant defective for integrin binding, showing that kindlin-3-mediated integrin signaling in blood cells is required for DVT. While platelet-specific deficiency of kindlin-3 in Kindlin-3fl/flPF4-Cre mice significantly suppressed DVT, deficiency of kindlin-3 specifically in myeloid cells in Kindlin-3fl/flLysM-Cre mice remarkably enhanced the early development of DVT, indicating that kindlin-3 in platelets and myeloid cells can play distinct roles in regulating DVT. Mechanistically, the levels of neutrophil extracellular traps (NETs) in plasma, a key DVT facilitator, were significantly elevated in Kindlin-3fl/flLysM-Cre mice upon the IVC stenosis; and treatment with either DNase I or PAD4 inhibitor could effectively compromise the enhancement of DVT in these mice, suggesting that kindlin-3 in neutrophils may affect DVT via restraining NET release. In addition, we found that the kindlin-3-integrin αIIbβ3 signaling in platelets was required to promote NET release. Together, our studies reveal that kindlin-3 in platelets and myeloid cells can differentially regulate DVT through orchestrating NET release, thus providing further mechanistic insights into DVT.

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Special Article

Cited by 47 publications

References 3 publications

Adhesion of Activated Platelets to Endothelial Cells: Evidence for a GPIIbIIIa-dependent Bridging Mechanism and Novel Roles for Endothelial Intercellular Adhesion Molecule 1 (ICAM-1), αvβ3 Integrin, and GPIbα

Adhesion of Activated Platelets to Endothelial Cells: Evidence for a GPIIbIIIa-dependent Bridging Mechanism and Novel Roles for Endothelial Intercellular Adhesion Molecule 1 (ICAM-1), αvβ3 Integrin, and GPIbα

Human endoglin as a potential new partner involved in platelet–endothelium interactions

Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice

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