VEGF, Transcriptional Networks and Vascular Inflammation

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Vascular endothelial growth factor (VEGF) is an endothelial cell (EC)-specific mitogen, and chemotactic agent, which is involved in wound repair, angiogenesis of ischemic tissue, tumor growth, microvascular permeability, vascular protection, and hemostasis. Over the past several years, there has been a major thrust towards developing therapies that either decrease VEGF levels or activity (e.g. Avastin in cancer), or increase VEGF (e.g. gene delivery strategies in ischemic heart disease). At the same time, there is increasing evidence that VEGF plays a role in modulating inflammation and coagulation. VEGF may alter EC phenotype through transcriptional and/or post-transcriptional mechanisms. Among the transcription factors that have been implicated in VEGF signaling are NF-kB, Egr-1, NF-AT, and GATA. The overall goal of this proposal is to identify the transcriptional mechanisms that underlie VEGF signaling in inflammation and coagulation. The first aim will explore mechanisms by which VEGF induces expression of VCAM-1 and ICAM-1. In the second aim, siRNA and dominant negative approaches will be employed to map links between VEGF-responsive transcription factors and target gene expression/cellular function. The third aims is dedicated to an in vivo analysis of VEGF-responsive transcriptional networks in health and disease, with a particular emphasis on sepsis. A more complete understanding of the transcriptional mechanisms by which VEGF is coupledto endothelial cell phenotype should provide a framework for tailoring and fine tuning therapeutic modalities in vascular disease states.