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. 1999 Sep;104(5):533-9.
doi: 10.1172/JCI7141.

A murine model of myocardial microvascular thrombosis

P D Christie  1 , J M Edelberg, M H Picard, A S Foulkes, W Mamuya, H Weiler-Guettler, R H Rubin, P Gilbert, R D Rosenberg
Affiliations

A murine model of myocardial microvascular thrombosis

P D Christie et al. J Clin Invest. 1999 Sep.

Abstract

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statistical model that may offer a foundation for examination of hemostasis-regulating gene interactions.

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Figures

Figure 1
Figure 1
Cardiac microvascular endothelial cell and cardiac myocyte culture. Protein analysis of the levels of TM, uPA, and tPA from cardiac microvascular endothelial cells cultured alone (open bars) and in the presence of cardiac myocytes (filled bars).
Figure 2
Figure 2
Echocardiography: short-axis view of mouse heart at end-diastole. (a) TM–/Pro animal. (b) tPA–/–TM–/Pro animal. RV, right ventricular cavity; LV, left ventricular cavity; a, anterior myocardial segment; s, septal segment; p, posterior segment; l, lateral segment.
Figure 3
Figure 3
Histology of heart. (a and c) Fibrin immunohistochemistry. Frozen tissue sections of tPA–/–TM–/Pro (a) and wild-type (c) mice were fixed in acidic formalin to wash out soluble fibrinogen/fibrin; reacted with the fibrinogen/fibrin-specific antibody; and counterstained with hematoxylin. The dark-brown horseradish peroxidase reaction product shows fibrin present in the macrovasculature. (b and d) Trichrome stain. Frozen tissue sections of tPA–/–TM–/Pro (b) and wild-type (d) mice were processed according to standard protocols (24). The tPA–/–TM–/Pro section shows myocardial infarct caused by the fibrin present in distal arteries. This tissue death is not present in the wild-type hearts. All images are sections from the LV wall of the heart. ×150.
See this image and copyright information in PMC

References

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