Arterial thrombosis, a major complication of atherosclerosis, is the leading cause of death in the Western world. Thrombosis in vivo is usually initiated when endoluminal disruption leads to exposure of subendothelial procoagulants such as tissue factor (TF) to flowing blood, with binding of TF to factor VIIa resulting in activation of factors IX and X and subsequent fibrin deposition. Tissue factor pathway inhibitor (TFPI), a Kunitz-type serine-protease inhibitor, uniquely modifies the coagulation cascade in vivo by binding in a two-step process to TF-factor VIIa catalytic complex and factor Xa forming a quaternary inhibitory complex which dampens further coagulation. We have recently demonstrated that in spite of TFPI expression in atherosclerotic plaque, TF activity predominates. Thus our working hypothesis is that there is a relative deficiency of TFPI in atherosclerotic plaque and that the imbalance between TF and TFPI is an important source of vascular thrombogenicity and may contribute to plaque development and progression. To further define the importance of this imbalance, we propose two major goals. First, we will generate genetically modified mice that overexpress TFPI in a targeted manner limited to the vessel wall to determine whether altering the local balance favoring TF inhibition will inhibit arterial thrombosis and the development and progression of atherosclerosis. Second, to alter this balance in blood- derived cells, we will generate mice incapable of producing TFPI from circulating blood cells and test these mice in an established model of thrombosis.
Our Specific Aims are: 1) To generate transgenic mice which overexpress TFPI in a targeted manner, 2) To determine the role of vascular TFPI overexpression in the development of atherosclerosis, 3) To determine the role of vascular TFPI expression in a murine model of arterial thrombosis and 4) To determine the role of blood-derived TFPI expression in a murine model of arterial thrombosis. We anticipate that these studies will; 1) elucidate new mechanisms by which the balance between TF and TFPI regulates the development of atherosclerosis and thrombosis and 2) provide insights into the relative importance of blood-derived and circulating forms of TFPI. Ultimately these insights will lead to new therapeutic approaches to prevent and treat atherosclerosis and its most important complication, thrombosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL065191-01
Application #
6152953
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M1))
Program Officer
Jacobs, Tom P
Project Start
2000-09-05
Project End
2005-07-31
Budget Start
2000-09-05
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$253,061
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Holroyd, Eric W; Delacroix, Sinny; Larsen, Katarina et al. (2012) Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus. Arterioscler Thromb Vasc Biol 32:704-11
Holroyd, Eric W; White, Thomas A; Pan, Shuchong et al. (2012) Tissue factor pathway inhibitor as a multifunctional mediator of vascular structure. Front Biosci (Elite Ed) 4:392-400
Holroyd, Eric W; Simari, Robert D (2010) Interdependent biological systems, multi-functional molecules: the evolving role of tissue factor pathway inhibitor beyond anti-coagulation. Thromb Res 125 Suppl 1:S57-9
White, Thomas A; Witt, Tyra A; Pan, Shuchong et al. (2010) Tissue factor pathway inhibitor overexpression inhibits hypoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 43:35-45
White, Thomas A; Johnson, Tucker; Zarzhevsky, Natalia et al. (2010) Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis. Blood 116:1787-94
White, Thomas A; Pan, Shuchong; Witt, Tyra A et al. (2010) Murine strain differences in hemostasis and thrombosis and tissue factor pathway inhibitor. Thromb Res 125:84-9
Pan, Shuchong; White, Thomas A; Witt, Tyra A et al. (2009) Vascular-directed tissue factor pathway inhibitor overexpression regulates plasma cholesterol and reduces atherosclerotic plaque development. Circ Res 105:713-20, 8 p following 720
Sharma, Deepak K; Brown, Jennifer C; Choudhury, Amit et al. (2004) Selective stimulation of caveolar endocytosis by glycosphingolipids and cholesterol. Mol Biol Cell 15:3114-22
Gulati, Rajiv; Simari, Robert D (2004) Autologous cell-based therapies for vascular disease. Trends Cardiovasc Med 14:262-7
Gulati, Rajiv; Jevremovic, Dragan; Witt, Tyra A et al. (2004) Modulation of the vascular response to injury by autologous blood-derived outgrowth endothelial cells. Am J Physiol Heart Circ Physiol 287:H512-7

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