Atherosclerosis in Mice Is Not Affected by a Reduction in Tissue Factor Expression

Tilley, Rachel E.; Pedersen, Brian; Pawliński, Rafał; Sato, Yuichiro; Erlich, Jonathan; Shen, Yuechun; Day, Sharlene M.; Huang, Ying; Eitzman, Daniel T.; Boisvert, William A.; Curtiss, Linda K.; Fay, William P.; Mackman, Nigel

doi:10.1161/01.atv.0000202028.62414.3c

Cited by 36 publications

(31 citation statements)

References 51 publications

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“…In previous studies it was determined that a 50% reduction of TF, in all cells or in hematopoietic cells only in ApoE−/− and LDLR−/− mice, respectively, does not affect atherosclerosis development 50 . In our study we found that asTF overexpression increase neointima formation and lesion’s neovascularization following arterial injury in ApoE−/− mice fed a Western-type diet.…”

Section: Discussionmentioning

confidence: 99%

Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling

Giannarelli¹,

Alique²,

Rodriguez³

et al. 2014

Circulation

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Background Alternatively Spliced Tissue Factor (asTF) is a novel isoform of full-length Tissue Factor (fl-TF) that exhibits angiogenic activity. Although asTF has been detected in human plaques, it is unknown whether its expression in atherosclerosis causes increased neovascularization and an advanced plaque phenotype. Methods and Results Carotid (n=10) and coronary specimens (n=8), from patients with stable or unstable angina, were classified as complicated or uncomplicated based on plaque morphology. Analysis of asTF expression and cell type –specific expression revealed a strong expression and co-localization of asTF with macrophages and neovessels within complicated, but not un-complicated, human plaques. Our results showed that the angiogenic activity of asTF is mediated via HIF-1α up-regulation through integrins and activation of phosphatidylinositol-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways. HIF-1α up-regulation by asTF also was associated with increased VEGF expression in primary human endothelial cells, and VEGF-Trap significantly reduced the angiogenic effect of asTF in vivo. Furthermore, asTF gene transfer significantly increased neointima formation and neovascularization following carotid wire injury in ApoE−/− mice. Conclusions The results of this study provide strong evidence that asTF promotes neointima formation and angiogenesis in an experimental model of accelerated atherosclerosis. Herein, we demonstrate that the angiogenic effect of asTF is mediated via the activation of the HIF-1/VEGF signaling. This mechanism may be relevant to neovascularization, progression and associated complications of human atherosclerosis as suggested by the increased expression of asTF in complicated vs. uncomplicated human carotid and coronary plaques.

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Section: Discussionmentioning

confidence: 99%

Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling

Giannarelli¹,

Alique²,

Rodriguez³

et al. 2014

Circulation

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“…Moreover, newly formed microvessels within atherosclerotic plaques can lead to plaque growth and destabilization by promoting inflammation and haemorrhage, and TF, which is importantly involved in angiogenesis [95], may play a role in plaque neovascularization. Nevertheless, the development of atherosclerosis in heterozygous TF-knockout mice, which have a 50 % reduction in vascular TF activity, does not differ from that in control animals; moreover, a 90 % reduction in haematopoietic-cell-derived TF does not alter the development of atherosclerotic lesions either [145]. Thus TF does not appear to influence atherogenesis in mice under these conditions.…”

Section: Tf and Atherosclerosismentioning

confidence: 88%

Tissue factor: beyond coagulation in the cardiovascular system

2009

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TF (tissue factor) is the main trigger of the coagulation cascade; by binding Factor VIIa it activates Factor IX and Factor X, thereby resulting in fibrin formation. Various stimuli, such as cytokines, growth factors and biogenic amines, induce TF expression and activity in vascular cells. Downstream targets of these mediators include diverse signalling molecules such as MAPKs (mitogen-activated protein kinases), PI3K (phosphoinositide 3-kinase) and PKC (protein kinase C). In addition, TF can be detected in the bloodstream, known as circulating or blood-borne TF. Many cardiovascular risk factors, such as hypertension, diabetes, dyslipidaemia and smoking, are associated with increased expression of TF. Furthermore, in patients presenting with acute coronary syndromes, elevated levels of circulating TF are found. Apart from its role in thrombosis, TF has pro-atherogenic properties, as it is involved in neointima formation by inducing vascular smooth muscle cell migration. As inhibition of TF action appears to be an attractive target for the treatment of cardiovascular disease, therapeutic strategies are under investigation to specifically interfere with the action of TF or, alternatively, promote the effects of TFPI (TF pathway inhibitor).

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“…Tilley et al used heterozygous TF knockout mice, which exhibit either 50% reduction in vascular TF activity or a 90% reduction in hematopoietic cell-derived TF, and investigated the development of atherosclerotic lesions. Interestingly, equal amount of atherosclerotic lesions were observed in these mice, 110 raising the question whether TF, at least in rodents, plays a role in atherogenesis, or not. This question still needs to be further investigated.…”

Section: Tf and Atherosclerosismentioning

confidence: 96%

Tissue Factor and Cardiovascular Disease: Quo Vadis?

Berndt

Tanner

Lüscher

2010

Circ J

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The coagulation cascade represents a system of proteases responsible to maintain vascular integrity and to induce rapid clot formation after vessel injury. Tissue factor (TF), the key initiator of the coagulation cascade, binds to factor VIIa and thereby activates factor IX and factor X, resulting in thrombus formation. Different stimuli enhance TF gene expression in endothelial and vascular smooth muscle cells. In addition to these vascular cells, TF has recently been detected in the bloodstream in circulating cells such as leukocytes and platelets, as a component of microparticles, and as a soluble, alternatively spliced form of TF. Various cardiovascular risk factors like hypertension, diabetes, and dyslipidemia, increase levels of TF. In line with this observation, enhanced vascular TF expression occurs during atherogenesis, particularly in patients with acute coronary syndromes. (Circ J 2010; 74: 3 - 12)

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Atherosclerosis in Mice Is Not Affected by a Reduction in Tissue Factor Expression

Cited by 36 publications

References 51 publications

Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling

Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling

Tissue factor: beyond coagulation in the cardiovascular system

Tissue Factor and Cardiovascular Disease: Quo Vadis?

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