Extrahepatic High-Density Lipoprotein Receptor SR-BI and ApoA-I Protect Against Deep Vein Thrombosis in Mice

Brill, Alexander; Yesilaltay, Ayce; Meyer, Simon F. De; Kisucka, Janka; Fuchs, Tobias A.; Kocher, Olivier; Krieger, Monty; Wagner, Denisa D.

doi:10.1161/atvbaha.112.252130

Cited by 49 publications

(46 citation statements)

References 54 publications

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“…Recently, it has been shown that, in vivo, apoA‐I deficiency abrogates flow restriction–induced thrombosis in a mouse model of deep vein thrombosis, and intravenous human apoA‐I infusion in wild‐type mice decreases thrombi prevalence from 55% in vehicle‐infused mice to 0% 51. Figure 8A shows representative aggregation curves, obtained with a Chrono‐log Optical aggregometer.…”

Section: Resultsmentioning

confidence: 99%

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Milasan

Jean

Dallaire

et al. 2017

JAHA

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BackgroundSubcutaneously injected lipid‐free apoA‐I (apolipoprotein A‐I) reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without increasing high‐density lipoprotein–cholesterol concentrations. Lymphatic vessels are now recognized as prerequisite players in the modulation of cholesterol removal from the artery wall in experimental conditions of plaque regression, and particular attention has been brought to the role of the collecting lymphatic vessels in early atherosclerosis‐related lymphatic dysfunction. In the present study, we address whether and how preservation of collecting lymphatic function contributes to the protective effect of apoA‐I.Methods and ResultsAtherosclerotic Ldlr −/− mice treated with low‐dose lipid‐free apoA‐I showed enhanced lymphatic transport and abrogated collecting lymphatic vessel permeability in atherosclerotic Ldlr −/− mice when compared with albumin‐control mice. Treatment of human lymphatic endothelial cells with apoA‐I increased the adhesion of human platelets on lymphatic endothelial cells, in a bridge‐like manner, a mechanism that could strengthen endothelial cell–cell junctions and limit atherosclerosis‐associated collecting lymphatic vessel dysfunction. Experiments performed with blood platelets isolated from apoA‐I‐treated Ldlr −/− mice revealed that apoA‐I decreased ex vivo platelet aggregation. This suggests that in vivo apoA‐I treatment limits platelet thrombotic potential in blood while maintaining the platelet activity needed to sustain adequate lymphatic function.ConclusionsAltogether, we bring forward a new pleiotropic role for apoA‐I in lymphatic function and unveil new potential therapeutic targets for the prevention and treatment of atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Milasan

Jean

Dallaire

et al. 2017

JAHA

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“…VWF has been implicated in the pathogenesis of this disorder in epidemiologic studies 42,43 and in animal models. [44][45][46] ApoA-I protects mice from venous thrombosis, partly by suppressing endothelial activation, 47 presumably reducing VWF secretion. 18 In summary, we describe an important anti-adhesive, anti-thrombotic role for HDL/ApoA-I: the ability to interfere with VWF self-association and thereby reduce the length and thickness of VWF fibers, decreasing platelet adhesion.…”

Section: Discussionmentioning

confidence: 99%

High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion

Chung

Chen

Ling

et al. 2016

Blood

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• High-density lipoprotein and its major apolipoprotein ApoA-I prevent von Willebrand factor self-association. • Targeting von Willebrand factor self-association could be a new approach to treating thrombotic disorders.The ability of von Willebrand factor (VWF) to initiate platelet adhesion depends on the number of monomers in individual VWF multimers and on the self-association of individual VWF multimers into larger structures. VWF self-association is accelerated by shear stress. We observed that VWF self-association occurs during adsorption of VWF onto surfaces, assembly of secreted VWF into hyperadhesive VWF strings on the endothelial surface, and incorporation of fluid-phase VWF into VWF fibers. VWF adsorption under static conditions increased with increased VWF purity and was prevented by a component of plasma. We identified that component as high-density lipoprotein (HDL) and its major apolipoprotein ApoA-I. HDL and ApoA-I also prevented VWF on the endothelium from self-associating into longer strands and inhibited the attachment of fluid-phase VWF onto vessel wall strands. Platelet adhesion to VWF fibers was reduced in proportion to the reduction in selfassociated VWF. In a mouse model of thrombotic microangiopathy, HDL also largely prevented the thrombocytopenia induced by injection of high doses of human VWF. Finally, a potential role for ApoA-I in microvascular occlusion associated with thrombotic thrombocytopenic purpura and sepsis was revealed by the inverse relationship between the concentration of ApoA-I and that of hyperadhesive VWF. These results suggest that interference with VWF self-association would be a new approach to treating thrombotic disorders. are characterized by systemic endothelial activation and microvascular occlusion. In recent studies, von Willebrand factor (VWF) secreted from the endothelium as a result of systemic endothelial activation has been shown to contribute to microvascular dysfunction and occlusion. A portion of the newly secreted VWF remains attached to the endothelial surface, from which it is normally removed through cleavage by the plasma metalloprotease ADAMTS13. 6 However, when ADAMTS13 is inhibited, as during episodes of TTP, or when VWF removal is delayed, as in conditions of intense inflammation such as sepsis and malaria, 7 the secreted VWF self-associates into long, thick strands that bind platelets to form occlusive thrombi in the small blood vessels. 6 VWF synthesis is a complex process. VWF homodimers first form in the endoplasmic reticulum through disulfide bonds involving cysteine residues near the VWF carboxyl terminus. In the Golgi apparatus, these dimers are linked together into chains through disulfide bonds at the amino termini, producing a ladder of multimeric molecules, each differing from the next largest by the molecular mass of a VWF dimer. The largest multimers found in blood can be enormous, reaching a molecular mass of more than 20 million Da. These gargantuan molecules can form even larger structures by associating with other VWF multime...

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“…35 It should be noted, however, that there is significant variability in thrombosis observed in the IVC stenosis model. 35,53,[70][71][72] One study reported increased incidence of thrombosis in this model in C57BL/6J mice bearing subcutaneous PANC02 tumors. 73 In contrast, we did not observe an increase in IVC thrombosis in nude mice bearing TF-positive human HPAF-II pancreatic tumors.…”

Section: Tf-positive Mps In Animal Studiesmentioning

confidence: 93%

Tumor-derived tissue factor–positive microparticles and venous thrombosis in cancer patients

Geddings

Mackman

2013

Blood

284

238

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Patients with cancer have an increased risk for venous thrombosis. Interestingly, different cancer types have different rates of thrombosis, with pancreatic cancer having one of the highest rates. However, the mechanisms responsible for the increase in venous thrombosis in patients with cancer are not understood. Tissue factor (TF) is a transmembrane receptor and primary initiator of blood coagulation. Tumor cells express TF and spontaneously release TF-positive microparticles (MPs) into the blood. MPs are small membrane vesicles that are highly procoagulant. It has been proposed that these circulating tumor-derived, TF-positive MPs may explain the increased rates of venous thrombosis seen in patients with cancer. In animal models, increased levels of tumor-derived, TF-positive MPs are associated with activation of coagulation. Moreover, these MPs bind to sites of vascular injury and enhance thrombosis. We and others have found that patients with cancer have elevated levels of circulating TF-positive MPs. These MPs are derived from tumors because they express tumor markers and are decreased by tumor resection. Importantly, several studies have shown that increased levels of TF-positive MPs correlate with venous thrombosis in patients with cancer. Taken together, these results suggest that TF-positive MPs may be a useful biomarker to identify patients with cancer who are at high risk for thrombosis.

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Extrahepatic High-Density Lipoprotein Receptor SR-BI and ApoA-I Protect Against Deep Vein Thrombosis in Mice

Cited by 49 publications

References 54 publications

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion

Tumor-derived tissue factor–positive microparticles and venous thrombosis in cancer patients

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