The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Bochenek, Magdalena L.; Bauer, Tobias; Gogiraju, Rajinikanth; Nadir, Yona; Mann, Amrit; Schönfelder, Tanja; Hünig, Leonie; Brenner, Benjamin; Münzel, Thomas; Wenzel, Philip; Konstantinides, Stavros; Schäfer, Katrin

doi:10.1182/bloodadvances.2017014050

Cited by 17 publications

(15 citation statements)

References 78 publications

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“…76 Our study in mice shows the importance of p53 for the risk of thrombosis in vivo, especially in states of endothelial p53 upregulation, such as in increased age. 77 In this study, we could show that aging in mice was associated with p53 overexpression and apoptosis in endothelial cells lining the inferior vena cava (IVC). Moreover, aged mice developed more frequent and larger venous thrombi after being subjected to subtotal IVC ligation, whereas aged mice with endothelial-specific p53 deletion were protected from venous thrombosis.…”

Section: Novel Endothelial-derived Mediators Of Thrombosismentioning

confidence: 94%

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Role of Endothelial Cells in Acute and Chronic Thrombosis

Bochenek

Schäfer

2019

Hamostaseologie

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Haemostasis encompasses a set of strictly regulated actions, such as vasoconstriction, platelet activation and blood coagulation. Endothelial cells play a crucial role in all of these processes and are an integral part of the vascular response to injury resulting in thrombus formation. Healthy endothelium expresses mediators to prevent platelet activation, including prostacyclin and nitric oxide, and to inhibit coagulation, such as thrombomodulin or RNase1. Upon activation, endothelial cells expose von Willebrand factor, integrins and other receptors to interact with activated platelets, erythrocytes and coagulation factors, respectively, resulting in blood clot formation. The endothelial cell response to cytokines and growth factors released from activated platelets and immune cells abundantly present in arterial and venous thrombi also plays an important role for thrombus resolution, whereas failure to completely resolve thrombi may initiate fibrotic remodelling and chronic vascular occlusion both in the arterial and venous tree. Therefore, endothelial cells are increasingly recognized as potential target to prevent thrombotic events and to accelerate thrombus resolution. Here, we discuss recent publications from our group in the context of other studies on the role of the endothelium during acute and chronic thrombotic events.

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Section: Novel Endothelial-derived Mediators Of Thrombosismentioning

confidence: 94%

“…115 Although still at the experimental stage, we and others could establish the efficacy of potential novel therapeutic strategies, such as TFPI2 peptides, for their potential to limit the extent of acute venous thrombosis in mice. 77,83,84…”

Section: Antithrombotic Therapeutic Strategies Targeting the Endothelmentioning

confidence: 99%

Role of Endothelial Cells in Acute and Chronic Thrombosis

Bochenek

Schäfer

2019

Hamostaseologie

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“…Expression of p53 also stimulates PAI-1 secretion in endothelial cells (among other genes in endothelial cells). The effect of reducing fibrinolysis outweighs that of increasing collagenolysis, because overexpression of p53 increases thrombus size [227], and in aged mice an endothelial knockout of p53 protects against DVT [228]. However, genetic or pharmacologic inhibition of p53 impairs DVT resolution in younger adult mice, whereas the p53 agonist quinacrine accelerates this resolution [229].…”

Section: Collagenolysismentioning

confidence: 99%

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Nicklas

Gordon

Henke

2020

IJMS

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Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy. already progressed past the point of anticoagulant efficacy [12,13]. Thus, there is potential clinical utility in investigating and controlling the process by which DVTs resolve in order to provide better care to these later-stage patients, with less bleeding risk. Overview of Venous Thrombus Development in HumansThe time sequence of DVT development and resolution was correctly suggested as early as 1962, based on empirical stains that detected changes in the nanoscopic roughness of clotted material [14]. As Lendrum et. al. remarked, "we consider that the intracytoplasmic granules, which we think are engulfed fibrin, seen in pulmonary phagocytes and in the endothelium of arteries and veins containing thrombus, are better shown by this (methyl-scarlet-blue) method than by any of the others." In fresh clot (whether in deep veins or in diabetic kidneys), platelets and erythrocytes are initially linked in a fine mesh yielding a relatively smooth surface (stage 1). A mat of the medium-textured fibrin replaces the initial thrombus (stage 2), which is gradually replaced by much coarser collagen (stage 3). This staging of clot development quickly became the basis of a pathological guide to grade thrombi [15]. The current three-stage refinement of the DVT grading scheme indicates that the turnover of erythrocyte-rich to fibrin-rich clot in humans is complete approximately seven days after the initial thrombotic event [16], whereas fibrin deposition commences after one day [17]. Various leukocytes, initially neutrophils and later macrophages, are believed to control this progression of DVTs development from a mass of erythrocytes, to fibrin, and finally to collagen [18]. Infiltrating T-lymphocytes and macrophages conta...

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“…Recently, Bochenek et al showed in a model of endothelial senescence that inhibition of heparanase activity using the TFPI-2 peptides prevented enhanced venous thrombus formation in aged mice and restored it to the thrombotic phenotype of control adult mice. 62 Thus, heparanase inhibition could also potentially affect the course of aging in endothelial cells.…”

Section: Inhibition Of Heparanase Procoagulant Activitymentioning

confidence: 99%

Decreasing Tumor Growth and Angiogenesis by Inhibition of Coagulation

Nadir

2019

Semin Thromb Hemost

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Data regarding the effect of coagulation proteins on enhancing angiogenesis and tumor growth are ample. Thus, inhibition of the coagulation system in an attempt to reduce tumor growth and metastasis seems appealing. However, such molecules as direct oral anticoagulants, warfarin and heparins, may impose a bleeding tendency, limiting the treatment dose that can be used. The heparanase protein, as a cofactor for tissue factor (TF) activity, enhances activation of the coagulation system and in addition has several nonhemostatic effects increasing tumor growth. The molecules currently investigated in the field of cancer and coagulation are heparin mimetics and inhibitors of heparanase derived from TF pathway inhibitor 2. Both groups of molecules are inhibitors of heparanase and in addition pose a low bleeding tendency. Hence, interfering in heparanase activity seems to be a promising target for development of antitumor drugs.

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The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Cited by 17 publications

References 78 publications

Role of Endothelial Cells in Acute and Chronic Thrombosis

Role of Endothelial Cells in Acute and Chronic Thrombosis

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Decreasing Tumor Growth and Angiogenesis by Inhibition of Coagulation

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