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Nonproteolytic Properties of Murine Alternatively Spliced Tissue Factor: Implications for Integrin-Mediated Signaling in Murine Models

Year: 2012
Type: article
Abstract: This study was performed to determine whether murine alternatively spliced tissue factor (masTF) acts analogously to human alternatively spliced tissue factor (hasTF) in promoting neovascularization via integrin ligation. Immunohistochemical evaluation of a spontaneous murine pancreatic ductal adenocarcinoma model revealed increased levels of masTF and murine full-length tissue factor (mflTF) in tumor lesions compared with benign pancreas; furthermore, masTF colocalized with mflTF in spontaneous aortic plaques of Ldlr(-/-) mice, indicating that masTF is likely involved in atherogenesis and tumorigenesis. Recombinant masTF was used to perform in vitro and ex vivo studies examining its integrin-mediated biologic activity. Murine endothelial cells (ECs) rapidly adhered to masTF in a β3-dependent fashion. Using adult and embryonic murine ECs, masTF potentiated cell migration in transwell assays. Scratch assays were performed using murine and primary human ECs; the effects of masTF and hasTF were comparable in murine ECs, but in human ECs, the effects of hasTF were more pronounced. In aortic sprouting assays, the potency of masTF-triggered vessel growth was undistinguishable from that observed with hasTF. The proangiogenic effects of masTF were found to be Ccl2-mediated, yet independent of vascular endothelial growth factor. In murine ECs, masTF and hasTF upregulated genes involved in inflammatory responses; murine and human ECs stimulated with masTF and hasTF exhibited increased interaction with murine monocytic cells under orbital shear. We propose that masTF is a functional homolog of hasTF, exerting some of its key effects via β3 integrins. Our findings have implications for the development of murine models to examine the interplay between blood coagulation, atherosclerosis and cancer.
DOI: 10.2119/molmed.2011.00416
Authors: Richard C. Godby, Yascha W. van den Berg, Ramprasad Srinivasan, Robert Sturm, David Y. Hui, Stephen F. Konieczny, Bruce J. Aronow, Evgeny Ozhegov, Wolfram Ruf, Henri H. Versteeg, Vladimir Y. Bogdanov
Institutions: University of Cincinnati, Leiden University Medical Center, Purdue University West Lafayette, Purdue University Institute for Cancer Research, Cincinnati Children's Hospital Medical Center, Scripps Research Institute
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $3,190
Funders: Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: G1268122162, G194941591, Pancreas Transcription Factors and Disease Model Systems, Inducible transgenes expressing EJC enriched mRNAs: a post-genomic innovation, Kras-Induced Cellular Plasticity in Pancreatic Cancer, G6371332694, Cincinnati Center for Clinical and Translational Sciences and Training, Short-Term Institutional Research Training Grant
OpenAlex ID: W1568664552
FWCI: 2.365
Cites: 46
Cited by: 13
Related to: 10