Chagas' disease, caused by the parasite T. cruzi (TC), is an important cause of heart disease. We have identified discrete cellular processes which appear to be the targets of TC infection which share in common an integrated role in the maintenance of microvascular perfusion. The biochemical basis for the compromise in microvascular perfusion will be studied. We will focus on the major cellular components of the microvasculature, namely the endothelial cell and the vascular smooth muscle cell. We will study the influence of T. cruzi infection on endothelial cell derived products that modulate vascular tone including endothelin (ET-1) and EDRF/NO. We will also determine whether the administration of the ET-1 antagonists (BQ-123) and, oligonucleotides antisense to ET-1 will modulate the development of chagasic heart disease in vivo. We will examine the influence of infection on endothelial cell receptors involved in the modulation of microvascular perfusion and study the influence of T. cruzi infection on gap junction-mediated intercellular communication of endothelial cells. We have shown that the extracellular matrix (ECMi) derived from infected endothelial cells alters certain synthetic properties of uninfected endothelial cells. We will extend these observations by determining the influence of ECMi on the synthesis of ET- 1, EDRF, surface receptors and intercellular communication on uninfected endothelial cells. The interrelationship between endothelial cells and vascular smooth muscle cells in the maintenance of microvascular function in T. cruzi infection will be examined by employing in vitro techniques to directly assess the influence of T. cruzi infection on the endothelial cell vascular smooth muscle interaction.
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