Tissue factor pathway inhibitor as a multifunctional mediator of vascular structure

Abstract

Tissue factor pathway inhibitor (TFPI) is a potent regulator of tissue factor -factor VII-dependent activation of the tissue factor pathway. TFPI is a serine protease inhibitor that contains three Kunitz domains and a basic carboxyl terminus. TFPI is primarily expressed on endothelial cells, and murine models have demonstrated that its expression regulates vascular thrombosis. The localization of TFPI expression and the requirement for TFPI in development suggest a potential role in regulating vascular structure. Data from animal studies suggest that vascular expression of TFPI inhibits pathologic vascular remodeling and inhibits angiogenesis. The mechanism for these effects is diverse and includes tissue factor and factor Xa-dependent and -independent mechanisms. KeywordsTissue factor; atherosclerosis; angiogenesis INTRODUCTIONThe vascular endothelium is a multimodal organ system that provides an integrating focus for the regulation of vascular structure and function. (1) Endothelial-derived nitric oxide would serve as a paradigm for this principle, functionally acting acutely to locally vasodilate vessels but also chronically on the underlying tunica media to affect both vascular structure and function. Other endothelial-derived molecules demonstrate similar multimodal properties. As the interface with blood, the endothelium is exposed to circulating factors and cells, as well as physical forces, which regulate thrombosis. The endothelium integrates proand anti-thrombotic signals to regulate local thrombogenicity. Endothelial cells express tissue factor pathway inhibitor (TFPI), a serine protease inhibitor which is the primary inhibitor of tissue factor (TF)-mediated coagulation. The functionality of TFPI however extends beyond this anticoagulant role, to regulate different aspects of vascular biology. This review will highlight human and experimental data which suggest that TFPI regulates macro and microvessel structure in a diverse manner.Address for correspondence: Robert D. Simari, M.D., Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA, simari.robert@mayo.edu. This is an, un-copyedited, author manuscript that has been accepted for publication in the Frontiers in Bioscience, http:// www.bioscience.org/2012/V4e/af/386/fulltext.htm. This article may not be duplicated or reproduced, other than for personal use or within the rule of "Fair Use of Copyrighted Materials" (section 107, Title 17, U.S. Code) without permission of the copyright holder, the Frontiers in Bioscience. From the time of acceptance following peer review, the full final copy edited article of this manuscript will be made available at http://www.bioscience.org/. The Frontiers in Bioscience disclaims any responsibility or liability for errors or omissions in this version of the un-copyedited manuscript or in any version derived from it by the National Institutes of Health or other parties." NIH Public Access Author ManuscriptFront Biosci (Elite Ed). Author manuscript; available in PMC 201...