We have identified a set of unique microvascular endothelial cells (CMEC) comprising approximately 10-20% of cardiac EC in mice, that express the vWF2 transgene. The transgene is expressed only in the microvessels of the heart and brain. Utilizing a combination of vitro and in vivo techniques, we have reported that gene expression of VEGF, Flk- 1, and vWF is under the control of one or more soluble myocyte factor(s) which induce neighboring EC to produce the PDGF-B subunit. We have also demonstrated that the latter component, subsequently, combines with the constitutively expressed PDGF-A subunit to form the PDGF-AB heterodimer. The PDGF-AB heterodimer, in turn, interacts with cells that possess the PDGF-alpha receptor to initiate transcription of genes for VEGF, Flk-1, and vWF, which characterize this unique CMEC population. This study will employ this population of cells to examine the roles of soluble factors, novel gene products and novel cell surface components which serve to initiate the transcription of VEGF, Flk-1, TF and vWF via the PDGF-alpha Receptor Circuit and thereby initiated the migration and proliferation of these cells under in vitro conditions. The signaling circuit is unique in that it coordinates the expression of a number of angiogenic factors such that they can collectively act upon EC and CMEC. In addition, it employs tissue specific cells within the organ to control the function of the angiogenic cascade. We also propose to identify and characterize the soluble factors and novel gene products, other than vWF, VEGF and Flk-1 which are critical for CMEC proliferation and migration under in vitro conditions, and that initiate angiogenesis and cardiac microvessels and macrovessels under normal in vivo conditions as well as prior to and during myocardial infarction. These interactions provide a new paradigm in which the organ, itself, regulates the extent of it's own angiogenesis.
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