Alternatively spliced tissue factor promotes plaque angiogenesis through the activation of hypoxia-inducible factor-1α and vascular endothelial growth factor signaling.

Abstract

BACKGROUND:

Alternatively spliced tissue factor (asTF) is a novel isoform of full-length tissue factor, which 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 (n=8) specimens from patients with stable or unstable angina were classified as complicated or uncomplicated on the basis of plaque morphology. Analysis of asTF expression and cell type-specific expression revealed a strong expression and colocalization of asTF with macrophages and neovessels within complicated, but not uncomplicated, human plaques. Our results showed that the angiogenic activity of asTF is mediated via hypoxia-inducible factor-1α upregulation through integrins and activation of phosphatidylinositol-3-kinase/Akt and mitogen-activated protein kinase pathways. Hypoxia-inducible factor-1α upregulation by asTF also was associated with increased vascular endothelial growth factor expression in primary human endothelial cells, and vascular endothelial growth factor-Trap significantly reduced the angiogenic effect of asTF in vivo. Furthermore, asTF gene transfer significantly increased neointima formation and neovascularization after 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. Here, we demonstrate that the angiogenic effect of asTF is mediated via the activation of the hypoxia-inducible factor-1/vascular endothelial growth factor signaling. This mechanism may be relevant to neovascularization and the progression and associated complications of human atherosclerosis as suggested by the increased expression of asTF in complicated versus uncomplicated human carotid and coronary plaques.

• Authors: Chiara Giannarelli, Matilde Alique, David T Rodriguez, Dong Kwon Yang, Dongtak Jeong, Claudia Calcagno, Randolph Hutter, Antoine Millon, Jason C Kovacic, Thomas Weber, Peter L Faries, Gerald A Soff, Zahi A Fayad, Roger J Hajjar, Valentin Fuster, Juan J Badimon
• Journal: Circulation (Circulation) Vol. 130 Issue 15 Pg. 1274-86 (Oct 07 2014) ISSN: 1524-4539 [Electronic] United States
• PMID: 25116956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Apolipoproteins E
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Vascular Endothelial Growth Factor A
• Thromboplastin

Topics

• Alternative Splicing (physiology)
• Animals
• Apolipoproteins E (deficiency, genetics)
• Carotid Arteries (pathology, physiopathology)
• Coronary Vessels (pathology, physiopathology)
• Disease Models, Animal
• Endothelium, Vascular (pathology, physiopathology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Neointima (physiopathology)
• Neovascularization, Pathologic (physiopathology)
• Plaque, Atherosclerotic (pathology, physiopathology)
• Signal Transduction (physiology)
• Thromboplastin (physiology)
• Up-Regulation (physiology)
• Vascular Endothelial Growth Factor A (physiology)