Regulation of pericytes by Angiopoietin2-studies in new animal models

视网膜病变是糖尿病最常见的微血管并发症。高血糖引起的视网膜毛细血管损伤的最早迹象是周细胞的丢失。周细胞募集作为血管成熟的重要组成部分，涉及多个配体-受体系统，其中包括血管生成素-Tie系统。Tie2介导其两个配体Angiopoietin 1和2的双重作用，其中Ang 1(Ang 1)激活Tie2而Ang 2(Ang 2)似乎是Ang-1的天然拮抗剂。为了更好地理解和为未来的干预提供可能的基础，我们建议建立并鉴定在光感受器视蛋白启动子控制下过度表达Ang2的转基因小鼠，在该转基因小鼠中，周细胞招募、视网膜毛细血管重塑和血管退化在出生后发育、糖尿病和低氧诱导的增殖性视网膜病变期间进行研究。这个转基因小鼠品系将与在周细胞特异性启动子下表达报告基因LacZ的转基因品系杂交。该模型能够研究血管紧张素转换酶2对周细胞的调节作用。利用第三只在血管紧张素转换酶启动子下表达LacZ的转基因小鼠，我们将研究血管紧张素转换酶2在糖尿病早期周细胞丢失中的功能作用。Ang2的表达可通过多种途径进行调节，包括血管紧张素受体抑制、HB-EGF激活抑制、EGF受体调节和活性氧。Ang 2修饰剂的这些靶点将在使用Ang 2物种的体内模型中进行测试。Ang 2修饰剂的这些靶点将在体内模型中进行测试，使用Ang 2的表达和早期糖尿病的周细胞招募作为标记物。综上所述，我们将结合发育中的视网膜分析以及糖尿病和增殖性视网膜病变中的视网膜分析与新的转基因小鼠模型相结合，该模型的共同点是血管紧张素转换酶2的调节。

Retinopathy is the most prevalent microvascular complication in diabetes. The earliest indication of hyperglycemia-induced retinal capillary damage is the loss of pericytes. Pericyte recruitment as an important part of vessel maturation involves several ligand-receptor systems including the Angiopoietin-Tie system. Tie2 mediates the dual effects of its two ligands angiopoietin 1 and 2, in which angiopoietin 1 (Ang 1) activates Tie2 while angiopoietin 2 (Ang 2) appears to be a natural antagonist of angiopoietin-1. For a better understanding and a possible basis for future interventions, we propose to establish and characterize a transgenic mouse which overexpresses Ang 2 under control of the photoreceptor opsin promoter in which pericyte recruitment, retinal capillary remodelling, and vascular regression is studied during postnatal development, in diabetes, and during hypoxia-induced proliferative retinopathy. This transgenic mouse line will be crossbred to a transgenic line which expresses the reporter gene LacZ under a pericytespecific promoter. This model enables to study pericyte modulation by Ang 2. Using a third transgenic mouse which expresses LacZ under the Ang 2 promoter, we will study the functional role of Ang2 in early diabetic pericyte loss. Ang 2 expression is modifiable by a variety of approaches, including Angiotensin receptor inhibition, inhibition of HB-EGF activation, EGF-receptor modulation and by reactive oxygen species. These targets of Ang 2 modifiers will be tested in in vivo models using Ang 2 species. These targets of Ang 2 modifiers will be tested in in vivo models using Ang 2 expression and pericyte recruitment in early diabetes as markers. In summery, we will combine retinal analysis in development, and in diabetic and proliferative retinopathy with new transgenic mouse models whose common denominator is the modulation of Ang 2.