Deficiency of Tissue Factor Pathway Inhibitor Promotes Atherosclerosis and Thrombosis in Mice

Westrick, Randal J.; Bodary, Peter F.; Xu, Zhigang; Shen, Yue; Broze, George J.; Eitzman, Daniel T.

doi:10.1161/hc2501.092492

Cited by 142 publications

(131 citation statements)

References 23 publications

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…Previous studies have demonstrated that loss of TFPI promotes vascular thrombosis,33 thus the elevated expression of TFPI and PTGIS in the apex may inhibit thrombosis at a location at which OSI is elevated, WSS is low, and blood residence time is significantly increased. These data contrast with reports of arterial EC experiments in vitro that showed no effect of oscillatory flow on TFPI gene expression 34, 35, 36.…”

Section: Discussionmentioning

confidence: 99%

Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome

McCormick

Manduchi

Witschey

et al. 2016

JAHA

View full text Add to dashboard Cite

BackgroundUnlike arteries, in which regionally distinct hemodynamics are associated with phenotypic heterogeneity, the relationships between endocardial endothelial cell phenotype and intraventricular flow remain largely unexplored. We investigated regional differences in left ventricular wall shear stress and their association with endocardial endothelial cell gene expression.Methods and ResultsLocal wall shear stress was calculated from 4‐dimensional flow magnetic resonance imaging in 3 distinct regions of human (n=8) and pig (n=5) left ventricle: base, adjacent to the outflow tract; midventricle; and apex. In both species, wall shear stress values were significantly lower in the apex and midventricle relative to the base; oscillatory shear index was elevated in the apex. RNA sequencing of the endocardial endothelial cell transcriptome in pig left ventricle (n=8) at a false discovery rate ≤10% identified 1051 genes differentially expressed between the base and the apex and 327 between the base and the midventricle; no differentially expressed genes were detected at this false discovery rate between the apex and the midventricle. Enrichment analyses identified apical upregulation of genes associated with translation initiation including mammalian target of rapamycin, and eukaryotic initiation factor 2 signaling. Genes of mitochondrial dysfunction and oxidative phosphorylation were also consistently upregulated in the left ventricular apex, as were tissue factor pathway inhibitor (mean 50‐fold) and prostacyclin synthase (5‐fold)—genes prominently associated with antithrombotic protection.ConclusionsWe report the first spatiotemporal measurements of wall shear stress within the left ventricle and linked regional hemodynamics to heterogeneity in ventricular endothelial gene expression, most notably to translation initiation and anticoagulation properties in the left ventricular apex, in which oscillatory shear index is increased and wall shear stress is decreased.

show abstract

Section: Discussionmentioning

confidence: 99%

Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome

McCormick

Manduchi

Witschey

et al. 2016

JAHA

View full text Add to dashboard Cite

show abstract

“…We previously have demonstrated that heterozygous Tfpi deficiency in mice affected time to occlusive thrombosis after endothelial injury at the site of an atherosclerotic plaque. 11 However, no difference in the time to occlusion was noted in the absence of preexisting vascular disease. In the present study, we have demonstrated that heterozygous Tfpi deficiency is uniformly lethal in mice that are also homozygous for FvL, whereas neither defect alone results in significant mortality.…”

Section: Mating Pairsmentioning

confidence: 96%

“…15 Tissue fibrin(ogen) staining was graded by a blinded observer using a qualitative scale roughly corresponding to the amount of stainable fibrin(ogen) as a percentage of each section (0, 0%; 1, 1% to 10%; 2, 11% to 50%; and 3, 51% to 100%). Adult mice were perfusion fixed as previously described, 11 and multiple organs were sectioned and stained with H&E.…”

Section: Histologymentioning

confidence: 99%

“…Animal studies have demonstrated an important in vivo regulatory role of TFPI in vascular thrombosis. 10,11 Variations in TFPI expression may be particularly important in the setting of other prothrombotic risk factors. In a synthetic in vitro assay of thrombin generation, reduction of TFPI concentration by 50% resulted in a slight increase in thrombin generation.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Lethal Perinatal Thrombosis in Mice Resulting From the Interaction of Tissue Factor Pathway Inhibitor Deficiency and Factor V Leiden

Eitzman

Westrick

et al. 2002

Circulation

Self Cite

View full text Add to dashboard Cite

Background — Factor V Leiden (FVL) is a common genetic risk factor for thrombosis in humans. The incomplete penetrance of FVL suggests important contributions from other genetic or environmental modifying factors. Variation in the expression of tissue factor pathway inhibitor ( TFPI ) has also been proposed as a risk factor for venous thrombosis and has been shown to enhance the prothrombotic effect of FVL in vitro. Methods and Results — To examine the potential in vivo interaction between Tfpi and FvL , we analyzed crosses between mice carrying FvL and a deficiency of TFPI. The Fv Q/Q , Tfpi +/− genotype was nearly completely fatal in the early perinatal period. Increased fibrin deposition was observed in multiple organs from the Fv Q/Q , Tfpi +/− fetuses, suggesting disseminated thrombosis. Conclusions — These observations demonstrate the prothrombotic effect of modest variations in the level of TFPI expression and suggest that TFPI could be an important genetic modifier for the thrombosis associated with FVL in humans.

show abstract

“…The surface area occupied by atherosclerosis was then quantitated at the thoracic aorta and major branches, including the brachiocephalic, carotid, and subclavian arteries, via Oil Red O staining and quantitative morphometry, as described previously. 15 The lesion area was calculated for the control and treatment groups and expressed as a percentage of total surface area examined (nϭ10 per group). Additional analysis of lesion thickness was performed on hematoxylin and eosin-stained cross-sections obtained from the ascending aorta and brachiocephalic and carotid arteries.…”

Section: Analysis Of Atherosclerosismentioning

confidence: 99%

Recombinant Leptin Promotes Atherosclerosis and Thrombosis in Apolipoprotein E–Deficient Mice

Bodary

Shen

et al. 2005

ATVB

Self Cite

122

View full text Add to dashboard Cite

Objective-The direct role of leptin in vascular disease remains controversial. The objective of this study was to examine the effects of leptin treatment on atherosclerosis and thrombosis in atherosclerotic-prone mice. Methods and Results-Sixteen-week-old, male apolipoprotein E-deficient mice were treated with injections of recombinant leptin (125 g per day IP; nϭ10) or vehicle (nϭ10) 4 and platelets. 5 Plasma leptin levels have also been correlated with cardiovascular complications in humans, an effect independent of body mass index and traditional risk factors. 6 -8 Nevertheless, the direct role of leptin in vascular disease remains controversial. Atherosclerotic mouse models with complete deficiency of leptin suggest that the absence of leptin might promote atherosclerosis. 9,10 However, these studies have been confounded by the extreme obesity and dyslipidemia that result from the loss of leptin-mediated central effects. 9,10 As a result, the direct effect of leptin on atherosclerosis has not yet been addressed. Therefore, to examine the direct role of leptin in atherosclerosis, we analyzed the effect of exogenous recombinant murine leptin on atherosclerosis using apolipoprotein E (apoE)-deficient mice.In addition, we tested the effects of chronic leptin therapy on thrombosis in these atherosclerotic-prone mice to determine whether potential metabolic improvements achieved with leptin therapy would outweigh the acute prothrombotic effect of leptin described previously. 11,12 Methods MiceMale apoE-deficient mice were purchased from the Jackson Laboratory (stock No. 002052; Bar Harbor, Maine) and provided Western chow (TD88137; Harlan Teklad) from 14 to 20 weeks of age. All procedures complied with the principles of laboratory and animal care established by the National Society for Medical Research and were approved by the University of Michigan committee on use and care of animals. Leptin TreatmentBeginning at 16 weeks of age, mice received 200 L intraperitoneal injections daily of either 125 g of recombinant murine leptin (R & D Systems) or vehicle control (nϭ10 per group). The dose of leptin chosen was based on a protocol used to achieve weight loss and fertility in leptin-deficient mice. 13 We determined that a 4-week duration of injections at this dose would be adequate to test the hypothesis that leptin promotes atherosclerosis in this particular model of hyperlipidemia. 14 http://atvb.ahajournals.org/ Downloaded from esthesia (100 mg/kg). Mice were perfused with saline and fixed using formalin with a 25-gauge needle inserted into the left ventricle at a rate of 1 mL/min. After formalin fixation, the arterial tree was meticulously dissected from the carcass and placed in 70% ethanol for Ն72 hours. The surface area occupied by atherosclerosis was then quantitated at the thoracic aorta and major branches, including the brachiocephalic, carotid, and subclavian arteries, via Oil Red O staining and quantitative morphometry, as described previously. 15 The lesion area was calculated for the control and treat...

show abstract

Deficiency of Tissue Factor Pathway Inhibitor Promotes Atherosclerosis and Thrombosis in Mice

Cited by 142 publications

References 23 publications

Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome

Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome

Lethal Perinatal Thrombosis in Mice Resulting From the Interaction of Tissue Factor Pathway Inhibitor Deficiency and Factor V Leiden

Recombinant Leptin Promotes Atherosclerosis and Thrombosis in Apolipoprotein E–Deficient Mice

Contact Info

Product

Resources

About