Expression and Function of Ephrin-B1 and Its Cognate Receptor EphB2 in Human Abdominal Aortic Aneurysm

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Abstract

We examined the expression of ephrin-B1 and its cognate receptor EphB2, key regulators of angiogenesis and embryogenesis, in human abdominal aortic aneurysm (AAA) and analyzed their functional roles in cell migration. From 10 patients (9 males and 1 female; age, 68.5 ± 2.4) who underwent vascular surgery for AAA, we obtained AAA and adjacent control tissues. Using real-time RT-PCR, we analyzed expression of ephrin-B1 and EphB2. We also histologically localized these molecules in AAA tissues. Finally, effects of ephrin-B1 and EphB2 on inflammatory cell chemotaxis were examined by cell migration assay. Expression levels of ephrin-B1 (0.410 ± 0.046 versus 1.198 ± 0.252, P = 0.027) and EphB2 (0.764 ± 0.212 versus 1.272 ± 0.137, P = 0.594) were higher in AAA than normal control. Both ephrin-B1 and EphB2 were expressed in macrophages, T lymphocytes, and endothelial cells within AAA. In chemotaxis assay, ephrin-B1 and EphB2 inhibited mononuclear-cell chemotaxis induced by stromal derived factor-1 down to 54.7 ± 12.7% ( P = 0.01) and 50.7 ± 13.1% ( P = 0.01), respectively. These data suggest that ephrin-B1 and EphB2 might be functional in human adult inflammatory cells and involved in the pathogenesis of AAA, although specific roles of these molecules should further be sought.

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Most cited references 34

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Inflammation and cellular immune responses in abdominal aortic aneurysms.

Koichi Shimizu, Richard N Mitchell, Peter Libby (2006)

Expansion and rupture of abdominal aortic aneurysms (AAA) result in high morbidity and mortality rates. Like stenotic atherosclerotic lesions, AAA accumulate inflammatory cells, but usually exhibit much more extensive medial damage. Leukocyte recruitment and expression of pro-inflammatory Th1 cytokines typically characterize early atherogenesis of any kind, and modulation of inflammatory mediators mutes atheroma formation in mice. However, the mechanistic differences between stenotic and aneurysmal manifestations of atherosclerosis remain unexplained. We recently showed that aortic allografts deficient in interferon-gamma (IFN-gamma) signaling developed AAA correlating with skewed Th2 cytokine environments, suggesting important regulatory roles for Th1/Th2 cytokine balance in modulating matrix remodeling and important implications for the pathophysiology of aortic aneurysm and atherosclerosis. Further probing of their distinct aspects of immune and inflammatory responses in vascular diseases should continue to shed new light on the pathophysiologic mechanisms that give rise to aneurysmal versus occlusive manifestations and atherosclerosis.

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Mouse models of abdominal aortic aneurysms.

Alan Daugherty, Lisa Cassis (2004)

Many mouse models of abdominal aortic aneurysms have been developed that use a diverse array of methods for producing the disease, including genetic manipulation and chemical induction. These models could provide insight into potential mechanisms in the development of this disease. Although experimental studies on abdominal aortic aneurysms (AAAs) have used a variety of mammalian and avian approaches, there is an increasing reliance on the use of mice. The models recapitulate some facets of the human disease including medial degeneration, inflammation, thrombus formation, and rupture. Most of the mouse models of AAA are evoked either by genetically defined approaches or by chemical means. The genetic approaches are spontaneous and engineered mutations. These include defects in extracellular matrix maturation, increased degradation of elastin and collagen, aberrant cholesterol homeostasis, and enhanced production of angiotensin peptides. The chemical approaches include the intraluminal infusion of elastase, periaortic incubations of calcium chloride, and subcutaneous infusion of AngII. A common feature of these models is the reduction of AAA incidence and severity by the prophylactic administration of matrix metalloproteinase (MMP) inhibitors or genetically engineered deficiencies of specific members of this proteolytic protein family. The validation of mouse models of AAAs will provide insight into the mechanisms of progression of the human disease.

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Restriction of receptor movement alters cellular response: physical force sensing by EphA2.

Khalid Salaita, Pradeep Nair, Rebecca Petit … (2010)

Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Vasc Med

Journal ID (iso-abbrev): Int J Vasc Med

Journal ID (publisher-id): IJVM

Title: International Journal of Vascular Medicine

Publisher: Hindawi Publishing Corporation

ISSN (Print): 2090-2824

ISSN (Electronic): 2090-2832

Publication date (Print): 2012

Publication date (Electronic): 5 July 2012

Volume: 2012

Electronic Location Identifier: 127149

Affiliations

¹Department of Vascular Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan

²Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa 920-8640, Japan

³Department of Pathology, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan

⁴Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565, Japan

Author notes

*Masakazu Yamagishi: myamagi@ 123456med.kanazawa-u.ac.jp

Academic Editor: Muredach P. Reilly

Article

DOI: 10.1155/2012/127149

PMC ID: 3398656

PubMed ID: 22830028

SO-VID: 0a10d2b8-133d-4836-b253-180a07177a96

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 29 March 2012

Date revision received : 22 May 2012

Date accepted : 6 June 2012

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Expression and Function of Ephrin-B1 and Its Cognate Receptor EphB2 in Human Abdominal Aortic Aneurysm

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Karger: Cardiovascular System

Most cited references 34

Inflammation and cellular immune responses in abdominal aortic aneurysms.

Mouse models of abdominal aortic aneurysms.

Restriction of receptor movement alters cellular response: physical force sensing by EphA2.

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