REGULATION OF CELL CYCLE PROTEINS DURING ANGIOGENESIS

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Angiogenesis plays a fundamental role in a number of processes such as development, wound healing and tumorigenesis. Although endothelial cell (EC) proliferation is a key event in angiogenesis, little is known about the regulation of molecules critical for this process. We postulate that 1) cell cycle proteins that control G1 transition of the cell cycle are regulated during angiogenesis and 2) some anti-angiogenic agents that inhibit EC growth affect proteins critical for G1 progression. We also postulate that 3) the extracellular matrix environment is important in regulating EC growth and that 4) distinct integrin receptors are responsible for triggering cell cycle proteins during this process. To investigate these hypotheses, we will monitor G1 phase cell cycle proteins during EC proliferation in vivo and in vitro. Initially we will establish a microvascular EC line with expanded life span by introducing telomerase. We will use these cells to determine 1) what G1 cell cycle proteins are expressed during mitogen-induced EC proliferation on different matrix proteins; 2) identify the integrins involved; 3) determine how integrin activation affects cell cycle proteins; 4) investigate the cell cycle events following treatment with anti-angiogenic agents. Furthermore, we will determine the expression patterns of G1 cell cycle proteins during angiogenesis in vivo. We also investigate the role of these proteins in angiogenesis by examining mice null for cell cycle proteins. Data derived from this study should provide specific insights to the mechanism of integrin-induced cell cycle progression and the role of cell cycle proteins during angiogenesis. Understanding the mechanism of anti-angiogenic agents and the molecular links between ligation and cell cycle machinery will aid in the development of new approaches to control angiogenesis-associated pathologies.