This project has two main objectives. The first deals with the metabolic properties and biosynthetic capabilities of human and bovine vascular endothelium (EC) and smooth muscle cells (SM) under normal conditions of culture and under conditions of in vitro injury. The response of EC and SM isolated from human umbilical vein and artery, and from bovine thoracic aorta to a) viral infection, b) viral transformation and c) tritiated thymidine shock will be examined in terms of changes of total and specific protein synthesis, such as type of collagen and fibronectin, and in terms of effects of extracellular matrix alteration on cell-matrix interaction. It is anticipated that changes in total protein and in the types of protein synthesized will vary with each type of virus and with each form of injury. Preliminary studies with each of these three forms of cell injury demonstrate changes in the genotypic and phenotypic expression with regard to collagen and fibronectin synthesis. It is our intent to characterize these changes in detail and attempt to correlate collagen and fibronectin synthesis with specific messenger-RNA in infected EC and SM and examine cell-matrix interaction after cell injury. The second main objective deals with the use of somatic cell hybrids of blood vessel cells in order to study regulation of synthesis and secretion of collagens, fibronectin and Factor VIII-antigen as well as to map the chromosomes in which the structural genes for these proteins reside. We propose that cell injury, whether in the form of viral infection, tritiated thymidine shock or of a chemical agent, is capable of initiating a series of cellular responses that result in the synthesis of quantitatively and/or qualitatively abnormal extracellular matrix components. An altered matrix could then initiate cellular responses which may lead to medial hypertrophy, thrombosis and/or atheromatous plaque formation. The experiments we propose should provide new knowledge on the regulation of synthesis and secretion of matrix components as well as on the response of vessel wall cells to injury with respect to extracellular protein synthesis and cell-matrix interaction.
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