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PLoS One. 2016 Jan 19;11(1):e0146586. doi: 10.1371/journal.pone.0146586. eCollection 2016.

Anthrax Toxin Receptor 1 Is Essential for Arteriogenesis in a Mouse Model of Hindlimb Ischemia.

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Frederik Meijer Heart and Vascular Institute, Spectrum Hospital, 100 Michigan St. NE, Grand Rapids, MI, 49503, United States of America.
Laboratory of Cancer and Developmental Cell Biology, Center for Cancer Cell Biology, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, 49503, United States of America.
Tumor Angiogenesis Section, Center for Cancer Research, National Cancer Institute, Bldg. 560, Frederick, MD, 21702, United States of America.
Partners in Science Program, Van Andel Education Institute, 333 Bostwick Ave NE, Grand Rapids, MI, 49503, United States of America.


Anthrax toxin receptor 1/tumor endothelial marker 8 (Antxr1 or TEM8) is up-regulated in tumor vasculature and serves as a receptor for anthrax toxin, but its physiologic function is unclear. The objective of this study was to evaluate the role of Antxr1 in arteriogenesis. The role of Antxr1 in arteriogenesis was tested by measuring gene expression and immunohistochemistry in a mouse model of hindlimb ischemia using wild-type and ANTXR1(-/-) mice. Additional tests were performed by measuring gene expression in in vitro models of fluid shear stress and hypoxia, as well as in human muscle tissues obtained from patients having peripheral artery disease. We observed that Antxr1 expression transiently increased in ischemic tissues following femoral artery ligation and that its expression was necessary for arteriogenesis. In the absence of Antxr1, the mean arterial lumen area in ischemic tissues decreased. Antxr1 mRNA and protein expression was positively regulated by fluid shear stress, but not by hypoxia. Furthermore, Antxr1 expression was elevated in human peripheral artery disease requiring lower extremity bypass surgery. These findings demonstrate an essential physiologic role for Antxr1 in arteriogenesis and peripheral artery disease, with important implications for managing ischemia and other arteriogenesis-dependent vascular diseases.

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