Although intravascular fibrin deposits and/or connective tissue accumulation are a common feature of vascular disorders, the underlying mechanisms remain obscure. The primary hypothesis of this proposal is that these changes result in part from a cytokine-mediated decrease in the fibrinolytic potential of cells of the vessel wall itself. This hypothesis will be tested by defining the fibrinolytic system of the vessel wall in vivo and determining whether it changes during experimentally induced or naturally occurring vascular disease. For example, the status of this system in endotoxemic mice, and in mice with bleomycin-mediated lung fibrosis, antibody-induced glomerulonephritis, and diet-induced atherosclerosis will be determined and compared to normal and diseased (e.g. atherosclerotic vessels) human tissues. The tissue distribution of tissue-plasminogen activator (t-PA), urokinase-PA (u-PA), PA-inhibitor 1 (PAI-1), PAI-2 and the u-PA receptor (u-PAR) will be investigated by employing specific antibodies in immunohistochemical studies to localize antigens, and specific cDNA probes in Northern blots and nuclease protection assays to quantitate mRNAs. In situ hybridization experiments will be performed using cRNA probes to each fibrinolytic component, and to von Willebrand's factor, in order to identify positive cells within the tissues, and to determine whether they are endothelial cells. The influence of infiltrating cells, and of cytokines released by them (e.g., tumor necrosis factor and transforming factor beta) on expression of this system during the progression of these diseases will be investigated. Finally, changes in the expression of these molecules in the tissues will be compared to changes in the blood to obtain insights into the origins of the plasma fibrinolytic components. These studies will begin to delineate the regulatory events controlling the individual fibrinolytic components in the tissues and blood under various conditions, and may contribute to our understanding of the influence of the fibrinolytic system on the prothrombotic state.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL047819-03
Application #
2223908
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1992-02-01
Project End
1996-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Giandomenico, G; Dellas, C; Czekay, R-P et al. (2005) The leptin receptor system of human platelets. J Thromb Haemost 3:1042-9
Konstantinides, Stavros; Schafer, Katrin; Neels, Jaap G et al. (2004) Inhibition of endogenous leptin protects mice from arterial and venous thrombosis. Arterioscler Thromb Vasc Biol 24:2196-201
Schafer, Katrin; Halle, Martin; Goeschen, Colin et al. (2004) Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol 24:112-7
Deng, Gary G; Martin-McNulty, Baby; Sukovich, Drew A et al. (2003) Urokinase-type plasminogen activator plays a critical role in angiotensin II-induced abdominal aortic aneurysm. Circ Res 92:510-7
Schafer, Katrin; Muller, Katja; Hecke, Anneke et al. (2003) Enhanced thrombosis in atherosclerosis-prone mice is associated with increased arterial expression of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 23:2097-103
Yamamoto, Koji; Shimokawa, Takayoshi; Yi, Hong et al. (2002) Aging accelerates endotoxin-induced thrombosis : increased responses of plasminogen activator inhibitor-1 and lipopolysaccharide signaling with aging. Am J Pathol 161:1805-14
Yamamoto, Koji; Takeshita, Kyosuke; Shimokawa, Takayoshi et al. (2002) Plasminogen activator inhibitor-1 is a major stress-regulated gene: implications for stress-induced thrombosis in aged individuals. Proc Natl Acad Sci U S A 99:890-5
Schafer, Katrin; Konstantinides, Stavros; Riedel, Carsten et al. (2002) Different mechanisms of increased luminal stenosis after arterial injury in mice deficient for urokinase- or tissue-type plasminogen activator. Circulation 106:1847-52
Takeshita, Kyosuke; Yamamoto, Koji; Ito, Masafumi et al. (2002) Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, ""Klotho"" mouse. Semin Thromb Hemost 28:545-54
Zhang, Lu; Seiffert, Dietmar; Fowler, Bruce J et al. (2002) Plasminogen has a broad extrahepatic distribution. Thromb Haemost 87:493-501

Showing the most recent 10 out of 44 publications