Targeting survival factors for ocular neovascularization

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DESCRIPTION: Vascular endothelial cells participating in neovascularization (NV) depend upon survival factors. If the survival factors are withdrawn or blocked, the endothelial cells undergo apoptosis and the NV regresses. Thus, identifying survival factors and finding ways to block them is a useful strategy for development of treatments for established NV. Right after sprouting, most types of NV tend to be very dependent upon vascular endothelial growth factor (VEGF) for survival, but over time the vessels mature and as part of the maturation process they acquire additional survival signals from extracellular matrix (ECM) and perivascular cells (pericytes). Defining these survival signals is an important goal. Two candidates are angiopoietin 1 (Ang1) acting through the Tie receptors on endothelial cells and platelet-derived growth factor-B (PDGF-B) acting through PDGF beta receptors on pericytes. Completely mature vessels tend to be less dependent upon VEGF, Ang1, and PDGF-B than new vessels, but this is a relative difference. For instance some normal vascular beds in adults, usually those that contain fenestrated vessels, still contain vessels that regress when VEGF is blocked. Also, while these molecules primarily target vascular cells they may also have survival-promoting effects for some neurons. Therefore, in order to target these survival signals to develop treatments for ocular NV, it is critical to determine the effect of blocking them on the normal retina and choroid as well as on ocular NV. We propose to do this using transgenic mice with inducible expression of potent blockers for each of the survival signals; soluble VEGF receptor 1 coupled to IgG Fc (VEGFtrap) to block VEGF, Ang2 to block Ang1, and soluble PDGF beta receptor coupled to IgG Fc (PDGFtrap) to block PDGF-B. The effect of expressing each of these antagonists alone and together will be examined both on choroidal NV that has been present for various amounts of time, and on the normal retina and choroid. Macrophages are another rich source of both survival and death signals for NV; therefore, we will use mice in which macrophages are ablated to determine their role in formation and regression of VEGF-induced ocular NV. This study addresses important public health problems, because it could lead to new treatments for established ocular NV which occurs in age-related macular degeneration and diabetic retinopathy, the most common causes of severe vision loss in the US.