Tissue Factor (TF), the initiator of the coagulation cascade, plays a critical role in hemostasis and thrombosis. There are numerous sources of TF in the vasculature, including macrophages, endothelial cells, and smooth muscle cells (SMC). In addition, TF circulates on procoagulant microparticles (MPs). It is likely that different sources of TF are critical to each pathologic process mediated by TF. This proposal focuses on SMC-derived TF. TF is regulated as a primary response to growth factors and cytokines in SMC, and is upregulated in arterial SMC in response to injury. TF has been implicated as a mediator of SMC migration and its inhibition reduces intimal hyperplasia in response to injury in a variety of animal models. TF is abundant in the media and intima of atherosclerotic plaques and SMC-derived TF is thought to contribute to the large burden of TF in the lipid-rich necrotic core. Therefore TF may play a role in plaque progression and may mediate thrombosis in association with plaque rupture. We have recently developed a mouse, TF/Sm221Cre, that has a >95% deficiency in SMC-derived TF. This mouse develops normally, has no obvious abnormalities of hemostasis, but has a marked reduction in arterial thrombosis induced by FeCl3 injury. SMC from these mice fail to migrate in response to factor (F) VIIa. Our preliminary data suggest that this mouse has reduced intimal hyperplasia in response to wire injury, and surprisingly develops more severe aneurysms in response to angiotensin II (Ang II). We hypothesize that SMC-derived TF may play a number of roles in mediating cardiovascular pathology, including direct effects on SMC physiology, indirect effects through the generation of thrombin, and as a source of procoagulant activity. The TF/Sm221Cre mouse enables us to explore the different roles of SMC-derived TF and determine the relative contribution of SMC- derived TF vs. circulating TF in a variety of pathologic states.
Aim 1 will determine the mechanism by which inhibition of SMC-derived TF leads to a reduction in intimal hyperplasia and utilize transplantation with bone marrow from mice with a 99% global reduction of TF and pharmacologic inhibition of TF to explore the relative contributions of SMC-derived and blood TF to this process.
This aim will also examine in depth FVIIa signaling in cultured SMC and determine the cellular mechanism(s) underlying TF-mediated SMC migration.
Aim 2 will establish the role of SMC-derived TF in mediating abdominal aortic aneurysms (AAA). To facilitate these experiments, the TF/Sm221Cre mice will be bred into the LDLR-/- background.
Aim 3 will utilize this mouse to determine the role of SMC-derived TF in mediating the development and progression of atherosclerosis.
Aim 4 will test the hypothesis that different types of thrombosis (macrovascular vs. microvascular, venous vs. arterial) involve different mechanisms and will further define the role of SMC-derived and circulating TF in these processes. These studies should help define the role of SMC-derived TF and circulating TF in mediating cardiovascular pathology and provide insights that may be useful in designing therapies targeted at TF.

Public Health Relevance

This proposal examines the biology of tissue factor, the molecule that initiates blood coagulation. Tissue factor is thought to play a major role in coronary thrombosis, the leading cause of heart attacks, and venous thromboembolism, the second leading cause of death in patients with cancer.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098391-04
Application #
8403981
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Tolunay, Eser
Project Start
2010-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$364,033
Indirect Cost
$128,413
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627