REGULATION OF MACROPHAGE ANGIOGENIC ACTIVITY

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It is well established that macrophages (M-phi) play a key role in the induction and maintenance of neovascularization during normal wound repair and are responsible in part for the aberrant endothelial proliferation that occurs in certain chronic inflammatory diseases such as psoriasis and neovascularization of solid tumors. More recently we have reported that activated M-phi produce the potent angiogenesis inhibitor thrombospondin-1 (TSP1). Although this observation would seem paradoxical we now have evidence that both murine and human monocyte- derived M~ undergo a "transition" from a potent proangiogenic to an equally potent angiostatic, TSP1 producing, phenotype. This would imply that M-phi can coordinate wound neovascularization. The hypothesis underlying the proposed work is that during normal wound repair M-phi function as both proangiogenic and angiostatic effector cells. The "transition" from the proangiogenic to the angiostatic phenotype parallels the expression pattern of the angiogenesis inhibitor TSP1. We further hypothesize that when Mphi fail to undergo this "transition" as in the chronic inflammatory skin disease psoriasis and during the development of solid tumors, this contributes significantly to the aberrant endothelial cell proliferation and neovascularization that is characteristic of these disorders. The specific aims of this proposal are: 1. To determine if macrophages (M-phi) during normal in vivo wound repair, (a) undergo a "transition" from a proangiogenic to an angiostatic phenotype, (b) if this event parallels the expression pattern of the angiostatic glycoprotein TSP1 and (c) if this transition enables Mphi to regulate wound neovascularization. 2. To examine the proangiogenic and angiostatic potential of wound- derived M-phi from TSP1 knockout mice. 3. To determine if psoriatic dermal endothelial cell proliferation and neovascularization of solid tumors are due in part to a failure of M-phi to undergo this "transition" from a proangiogenic to an angiostatic, TSP1 producing, phenotype. The studies proposed in this application should reveal new insights into the mechanism that coordinate the timely ingrowth and regression of new capillaries during wound repair, increase our understanding of the mechanism underlying the disregulated endothelial cell proliferation and neovascularization that occurs in psoriasis and solid tumor formation, and suggest novel strategies for the treatment of these and other angiogenesis/vasoproliferative-dependent disorders.