RETINAL NEOVASCULARIZATION IN DIABETIC RETINOPATHY

增殖性糖尿病视网膜病变的特征是视网膜血管阻塞和视网膜缺血，导致刺激新生血管的因子释放。起主要作用的一个因素是血管内皮生长因子(VEGF)。光感受器特异性表达血管内皮生长因子的转基因小鼠的新生血管起源于视网膜的深层毛细血管，而不是浅表的毛细血管或脉络膜血管。深毛细血管床在浅表毛细血管床和脉络膜血管之后发育，在转基因表达开始时仍在发育；由于其发育阶段，深毛细血管床可能对血管内皮生长因子更敏感。我们假设，仅有VEGF的过度表达并不足以刺激成熟血管的新血管生长，相反，必须通过在发育过程中或在缺血视网膜中表达的其他因素来使血管对VEGF更敏感。我们建议在转基因小鼠中使用四环素反应诱导反式激活系统和视网膜特异性启动子来验证这一假设。我们将确定血管内皮生长因子表达的时机或位置是否是新生血管模式的关键决定因素。我们还将探讨低氧诱导因子-1(HIF-1)、血管生成素1(Ang1)或Ang2是否在视网膜新生血管的形成中起作用。这些研究可以为视网膜新生血管的发生机制提供新的见解，并为治疗干预确定新的靶点。

Proliferative diabetic retinopathy is characterized by obstruction of retinal blood vessels and retinal ischemia leading to release of factors that stimulate neovascularization. One factor that plays a major role is vascular endothelial growth factor (VEGF). Transgenic mice with photoreceptor-specific expression of VEGF develop neovascularization originating from the deep capillaries of the retina, but not from the superficial capillaries or choroidal blood vessels. The deep capillary bed develops after the superficial capillary bed and choroidal vessels and is still developing at the time that the transgene expression begins; because of its developmental stage, the deep capillary bed may be more responsive to VEGF. We hypothesize that overexpression of VEGF alone is not sufficient to stimulate new vessel growth from mature blood vessels, but rather the vessels must be made more responsive to VEGF by other factors that are expressed during development or in ischemic retina. We propose to test this hypothesis using the tetracycline responsive inducible transactivation system in conjunction with retina-specific promoters in transgenic mice. We will determine if the timing or location of VEGF expression is a critical determinant of the pattern of neovascularization. We will also explore whether hypoxia-inducible factor-1 (HIF-1), Angiopoietin 1 (Ang1) or Ang2 play a role in the development of retinal neovascularization. These studies could provide new insights into mechanisms by which retinal neovascularization occurs and identify new targets for therapeutic intervention.