The Id proteins Id1 and Id3 have been shown to be essential for neovascularization of subcutaneous tumors in mice. These proteins, which inhibit the activity of basic helix loop helix transcription factors, have been shown by gene targeting experiments to be essential for the expansion of circulating endothelial cell precursors (CEPs) in the bone marrow (BM) and their mobilization into the periphery in response to elevated plasma levels of VEGF. The Id knockout mice have therefore been useful in modeling the effects of severe anti-angiogenic stress in adult animals. The current proposal is designed to expand these observations in several important ways. First, we will determine if BM derived CEPs vascularize spontaneous murine tumors since such models are much more physiologically relevant to human disease. The functional significance of such a contribution will also be tested by transplanting Id knockout animals with marked wild type BM. In addition, we will determine if Id loss in BM derived lin- stem cells is sufficient to confer the Id knockout phenotype in order to formally demonstrate the requirement for Id in BM derived angioblasts. Finally, we will identify Id target genes, which are misregulated in the BM of Id knockout animals in response to VEGF. These studies will further our understanding of the role of Id proteins in postnatal angiogenesis and more generally the molecular mechanisms of neoangiogenesis in spontaneous tumors.
