Targeting survival factors for ocular neovascularization

描述：血管内皮细胞参与新生血管（NV）依赖于生存因子。如果生存因子被撤回或阻断，内皮细胞发生凋亡，NV退化。因此，识别生存因素并找到阻断它们的方法是开发已建立的NV治疗方法的有用策略。发芽后，大多数类型的NV倾向于非常依赖血管内皮生长因子（VEGF）存活，但随着时间的推移，血管成熟，作为成熟过程的一部分，它们从细胞外基质（ECM）和血管周围细胞（周细胞）获得额外的生存信号。定义这些生存信号是一个重要的目标。两种候选药物是血管生成素1 （Ang1）通过内皮细胞上的Tie受体和血小板衍生生长因子b （PDGF- b）通过周细胞上的PDGF受体起作用。与新生血管相比，完全成熟的血管对VEGF、Ang1和PDGF-B的依赖性较低，但这是相对差异。例如，成年人的一些正常血管床，通常是那些含有开窗血管的血管，在VEGF被阻断时仍然含有退化的血管。此外，虽然这些分子主要针对血管细胞，但它们也可能对某些神经元具有促进生存的作用。因此，为了针对这些生存信号开发眼部NV的治疗方法，确定阻断它们对正常视网膜和脉络膜以及眼部NV的影响至关重要。我们建议使用转基因小鼠来实现这一目标，这些小鼠可诱导表达每种生存信号的有效阻断剂；可溶性VEGF受体1偶联IgG Fc （vegtrap）阻断VEGF，可溶性PDGF β受体偶联IgG Fc （pdgtrap）阻断PDGF- b。单独和共同表达这些拮抗剂的效果将在两种情况下进行研究

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 If the survival factors are withdrawn or blocked, the endothelial cells undergo apoptosis and the NV regresses.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.