The research objectives of this proposal include a study of the interactions between coagulation factors and vascular endothelial cells, with specific interest in mechanisms by which activation of coagulation may be regulated by endothelium. I have obtained preliminary information demonstrating that intact vascular endothelial cells, but not vascular smooth muscle cells, fibroblasts or corneal endothelial cells, inhibit blood coagulation. Having obtained these data and additional information that this inhibition occurs at the initial stage of activation of coagulation (contact pathway), I propose 1) to determine how vascular endothelial cells inhibit clotting by characterizing the component(s) in intact cells responsible for inhibition and identifying the coagulatino reaction(s) inhibited; 2) to characterize the binding of purified Factor Xa to specific sites on vascular endothelium; and 3) to determine the effects of other cells, such as fibroblasts and vascular smooth muscle cells as well as the extracellular matrix from endothelial cells, on blood coagulation and the mechanisms responsible for these effects. The methods to be used for this research will include purification of coagulation factors, X, XI and XII; establishment of endothelial cells as well as vascular smooth muscle cells in tissue culture, and production of extracellular matrix. Additionally, vascular cell components, including glycosaminoglycans, will be purified in order to study their effects on coagulation. Long-term research objectives also include using this experimental model to determine whether coagulation is modified after endothelial cell injury by pathologic stimuli, such as high concentrations of low density lipoproteins, neutrophil degranulation, or mechanical injury. These studies may identify previously unrecognized normal and pathological interactions between vascular cells and the coagulation system. Moreover, they may provide information which would enhance our understanding of the role of coagulation in atherogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001031-04
Application #
3081648
Study Section
(SRC)
Project Start
1982-07-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Rodgers, G M; Conn, M T (1990) Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 75:895-901
Rodgers, G M; Taylor, R N; Roberts, J M (1988) Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells. Am J Obstet Gynecol 159:908-14
Rodgers, G M; Kane, W H; Pitas, R E (1988) Formation of factor Va by atherosclerotic rabbit aorta mediates factor Xa-catalyzed prothrombin activation. J Clin Invest 81:1911-9
Stricker, R B; Lane, P K; Leffert, J D et al. (1988) Development of antithrombin antibodies following surgery in patients with prosthetic cardiac valves. Blood 72:1375-80
Rodgers, G M (1988) Vascular smooth muscle cells synthesize, secrete and express coagulation factor V. Biochim Biophys Acta 968:17-23
Rodgers, G M (1988) Hemostatic properties of normal and perturbed vascular cells. FASEB J 2:116-23
Rodgers, G M; Cong, J Y; Goll, D E et al. (1987) Activation of coagulation factor V by calcium-dependent proteinase. Biochim Biophys Acta 929:263-70
Rodgers, G M; Shuman, M A (1987) Enhancement of prothrombin activation on platelets by endothelial cells and mechanism of activation of factor V. Thromb Res 45:145-52
Rodgers, G M; Kane, W H (1986) Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 77:1909-16
Rodgers, G M; Shuman, M A (1986) Congenital thrombotic disorders. Am J Hematol 21:419-30

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