) Therapeutic angiogenesis attempts to change the course of diseases by altering the microvascular blood supply to the organs, either by reducing it in tumors. or increasing it in ischemic tissues. A new arsenal of methods is being developed including gene therapy for localized administration of angiogenic factors, efficient monoclonal antibodies against adhesion molecules; or cloned peptides mimicking the natural angiostatic mechanisms. However, the basic mechanisms governing the efficiency of these approaches are poorly understood. Here we suggest that a potent system for controlling angiogenesis is the monocyte/macrophage activity, which is essential for the progression of angiogenesis and tissue remodeling. We discovered that, when present in ischemic tissues, these cells produce long-lasting channels in the tissues they infiltrate. Our hypothesis is that these channels represent a prerequisite for angiogenesis in vivo, therefore are an ideal therapeutic target. In order to prove this new concept, and to bring it to practical applicability, the following specific aims will be pursued: 1) Model in vitro the formation of channels by monocytes/macrophages, and find the molecular factors on which this process depends. 2) Determine the influence that specific physiologic and pathologic conditions, thought to be associated with angiogenesis, have on the formation of channels by monocytes/macrophages in vitro. 3) Test the role the channel formation has in progression of angiogenesis in vitro. 4) reproduce in vivo and analyze the formation of channels in matrices of controlled composition. 5) test the possibility for therapeutic manipulation of angiogenesis in selected transgenic animals, by either using inhibitors of channel formation, or modifying tissue concentrations and/or distribution of monocytes (changing the distribution of chemotactic factors, or injecting concentrates of monocytes). To this end, we developed assays which will be used in vitro and in vivo for: a) characterization of molecular mechanisms of channel formation; b) the impact of channels system on angiogenesis; c) identification of compounds targeting the monocytes and macrophages, likely to influence the course of angiogenesis. The new approach for management of angiogenesis we suggest here, complements the current efforts in the field, bringing a broader understanding of basic mechanisms of angiogenesis and expending the spectrum of available therapeutic options.
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