Endothelial cell specific adhesion molecule (ESAM) localizes to platelet–platelet contacts and regulates thrombus formation in vivo

Stalker, Timothy J.; Wu, Jie; Morgans, Alicia K.; Traxler, Elizabeth A.; Wang, Leo; Chatterjee, Manash; Lee, D.; Quertermous, Thomas; Hall, Randy A.; Hammer, Daniel A.; Diamond, Scott L.; Brass, Lawrence F.

doi:10.1111/j.1538-7836.2009.03606.x

Cited by 60 publications

(55 citation statements)

References 36 publications

(61 reference statements)

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“…Gas6 produced by ECs was recently shown to influence venous thrombus formation through downregulation of TF expression. 46 Like BAMBI, other transmembrane proteins expressed in platelets and the endothelium can modulate thrombus growth and/or stability including platelet endothelial cell adhesion molecule (PECAM-1), 47 endothelial cell-selective adhesion molecule (ESAM), 48 junction adhesion molecule A (JAM-A), 49 and tetraspanin 151, 50 although for all of these, the attributed phenotype is associated with the platelet, rather than endothelial, pool of these receptors. In that regard, BAMBI appears to differ by influencing this process through its role in the endothelium.…”

Section: Discussionmentioning

confidence: 99%

Vessel wall BAMBI contributes to hemostasis and thrombus stability

Salles‐Crawley

Monkman

Ahnström

et al. 2014

Blood

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Key Points• This is the first report to describe the influence of BAMBI on both hemostasis and thrombus stability.• BAMBI present in the blood vessel wall (most likely the endothelium) rather than platelet BAMBI is required for thrombus stability.Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a transmembrane protein related to the transforming growth factor-b superfamily, and is highly expressed in platelets and endothelial cells. We previously demonstrated its positive role in thrombus formation using a zebrafish thrombosis model. In the present study, we used Bambi-deficient mice and radiation chimeras to evaluate the function of this receptor in the regulation of both hemostasis and thrombosis. We show that Bambi 2/2 and Bambi 1/2 mice exhibit mildly prolonged bleeding times compared with Bambi 1/1 littermates. In addition, using 2 in vivo thrombosis models in mesenterium or cremaster muscle arterioles, we demonstrate that Bambi-deficient mice form unstable thrombi compared with Bambi 1/1 mice. No defects in thrombin generation in Bambi 2/2 mouse plasma could be detected ex vivo. Moreover, the absence of BAMBI had no effect on platelet counts, platelet activation, aggregation, or platelet procoagulant function. Similar to Bambi 2/2 mice, Bambitransplanted with Bambi 1/1 bone marrow formed unstable thrombi in the laser-induced thrombosis model that receded more rapidly than thrombi that formed in Bambi 1/1 mice receiving Bambi 2/2 bone marrow transplants.Taken together, these results provide strong evidence for an important role of endothelium rather than platelet BAMBI as a positive regulator of both thrombus formation and stability. (Blood. 2014;123(18):2873-2881

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Section: Discussionmentioning

confidence: 99%

Vessel wall BAMBI contributes to hemostasis and thrombus stability

Salles‐Crawley

Monkman

Ahnström

et al. 2014

Blood

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“…37 It may also recruit a protein tyrosine phosphatase such as SHP1 or SHP2, as in the case of ITIM receptors such as PECAM-1, 38 or it may recruit a scaffolding protein such as NHERF-1, as shown in the case of ESAM, a CTX family member, 24 or recruit a negatively regulating kinase such as C-terminal Src kinase, Csk. 37 Several members of the CAM family have been show to exert an inhibitory effect on platelet function.…”

Section: Discussionmentioning

confidence: 99%

“…24 Fetal liver cells were isolated from 14-16 days after coitus and Jam-A gt/gt mice fetuses and injected retro-orbitally into lethally irradiated male Jam-A wt/wt recipients (Cesium-137, 10 Gy, Gammacell 40 Exactor; MDS Nordion). Intravital microscopy experiments were performed as described in the previous section 4 weeks after transplantation.…”

Section: Bm Transplantation Experimentsmentioning

confidence: 99%

“…To differentiate the contributions of platelet and endothelial cell Jam-A in impeding thrombus formation in vivo, we generated radiation chimera mice by injecting fetal liver cells isolated from Jam-A gt/gt or Jam-A wt/wt fetuses into lethally irradiated male Jam-A wt/wt recipients. 24 Mice receiving Jam-A gt/gt cells will have intact endothelial Jam-A, but lack platelet Jam-A. Successful reconstitution of hematopoiesis was confirmed by performing complete blood cell counts before intravital experiments.…”

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confidence: 99%

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JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets

Naik

Stalker

Brass

et al. 2012

Blood

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Mounting evidence suggests that agonistinitiated signaling in platelets is closely regulated to avoid excessive responses to injury. A variety of physiologic agonists induce a cascade of signaling events termed as inside-out signaling that culminate in exposure of high-affinity binding sites on integrin ␣ IIb ␤ 3 . Once platelet activation has occurred, integrin ␣ IIb ␤ 3 stabilizes thrombus formation by providing agonist-independent "outside-in" signals mediated in part by contractile signaling. Junctional adhesion molecule A (JAM-A IntroductionPlatelet activation is carefully regulated through both positive and negative regulators. 1 The ultimate result of platelet activation by agonist is conversion of integrin ␣ IIb ␤ 3 from its low-affinity state to a high-affinity state capable of binding soluble ligands such as fibrinogen through a process known as inside-out signaling. 2 Ligand binding to the activated integrin induces a cascade of signaling events known as outside-in signaling that stabilizes platelet aggregates and supports the process of clot retraction. 3 Timely and rapid activation of integrin is important for the process of hemostasis, but unwanted activation results in thrombosis. 4 Significant progress has been made toward understanding the process of agonist-induced platelet activation. 5 However, little is known about the process through which unwanted or accidental activation of integrin is discouraged. Here we show that junctional adhesion molecule A is a negative regulator of integrin function and provides protection from thrombosis.Junctional adhesion molecule A (JAM-A) was initially identified as a receptor for a platelet stimulatory mAb F11 (mAbF11) and it was shown that activation of platelets by this Ab occurs through cross-linking of JAM-A with Fc␥RIIA receptor on platelet surface. 6,7 Subsequently, it was been proposed that JAM-A may be regulating platelet function during thrombosis and atherosclerosis. [8][9][10][11] Prior work has shown that JAM-A is expressed on human and mouse platelets, where it can be found on the surface of both resting and activated platelets. 12 Later, JAM-A has been shown to be a member of the cortical thymocyte marker of the Xenopus (CTX) family of cell adhesion molecules (CAMs) that contains 2 extracellular Ig domains. 13 In addition to platelets, JAM-A is shown to be expressed on epithelial and endothelial cells as well as on leukocytes. 14 On epithelial and endothelial cells, JAM-A is exclusively localized to the tight junctions. 15,16 Although significant progress has been made in the elucidation of JAM-A function as a tight-junction protein, not much is known about its function on platelets that lack tight junctions.We generated a Jam-A knockout (Jam-A gt/gt ) mouse by disrupting F11r (Jam-A gene) using the gene-trap technique. 17,18 Using these mice, we show that Jam-A negatively regulates platelet function in vivo, as Jam-A-deficient mice show a prothrombotic phenotype. This gain of function is not because of the lack of endothelial Jam-A because tr...

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“…The deficiency also increases vascular permeability of the renal glomeruli, resulting in urinary albumin elevation (14). Additionally, it has been shown that ESAM is also expressed on megakaryocytes and platelets (12), where it is involved in the regulation of thrombus formation (15).…”

mentioning

confidence: 99%

The Endothelial Antigen ESAM Monitors Hematopoietic Stem Cell Status between Quiescence and Self-Renewal

Sudo

Yokota

Oritani

et al. 2012

The Journal of Immunology

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Whereas most hematopoietic stem cells (HSC) are quiescent in homeostasis, they actively proliferate in response to bone marrow (BM) injury. Signals from the BM microenvironment are thought to promote entry of HSC into the cell cycle. However, it has been cumbersome to assess cycle status of viable HSC and thus explore unique features associated with division. In this study, we show that expression of endothelial cell-selective adhesion molecule (ESAM) can be a powerful indicator of HSC activation. ESAM levels clearly mirrored the shift of HSC between quiescence and activation, and it was prominent in comparison with other HSC-related Ags. ESAMhi HSC were actively dividing, but had surprisingly high long-term reconstituting capacity. Immunohistochemical analyses showed that most ESAMhi HSC were located near vascular endothelium in the BM after 5-fluorouracil treatment. To determine the importance of ESAM in the process of BM recovery, ESAM knockout mice were treated with 5-fluorouracil and their hematopoietic reconstruction was examined. The ESAM deficiency caused severe and prolonged BM suppression, suggesting that ESAM is functionally indispensable for HSC to re-establish homeostatic hematopoiesis. With respect to intracellular regulators, NF-κB and topoisomerase II levels correlated with the ESAM upregulation. Thus, our data demonstrate that the intensity of ESAM expression is useful to trace activated HSC and to understand molecular events involved in stem cell states.

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Endothelial cell specific adhesion molecule (ESAM) localizes to platelet–platelet contacts and regulates thrombus formation in vivo

Cited by 60 publications

References 36 publications

Vessel wall BAMBI contributes to hemostasis and thrombus stability

Vessel wall BAMBI contributes to hemostasis and thrombus stability

JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets

The Endothelial Antigen ESAM Monitors Hematopoietic Stem Cell Status between Quiescence and Self-Renewal

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