Hammes Hans-Peter, Lin Jihong, Wagner Patrick, Feng Yuxi, Vom Hagen Franziska, Krzizok Thomas, Renner Oliver, Breier Georg, Brownlee Michael, Deutsch Urban
5th Medical Clinic, University-Clinic Mannheim, Medical Faculty of the University of Heidelberg, Heidelberg, Germany.
Diabetes. 2004 Apr;53(4):1104-10. doi: 10.2337/diabetes.53.4.1104.
Pericyte loss is an early pathologic feature of diabetic retinopathy, consistently present in retinae of diabetic humans and animals. Because pericyte recruitment and endothelial cell survival are controlled, in part, by the angiopoietin/Tie2 ligand/receptor system, we studied the expression of angiopoietin-2 and -1 in relation to the evolution of pericyte loss in diabetic rat retinae, using quantitative retinal morphometry, and in retinae from mice with heterozygous angiopoietin deficiency (Ang-2 LacZ knock-in mice). Finally, recombinant angiopoietin-2 was injected into eyes of nondiabetic rats, and pericyte numbers were quantitated in retinal capillaries. Angiopoietin-1 protein was present in the normal maturing retina and was upregulated 2.5-fold in diabetic retinae over 3 months of diabetes. In contrast, angiopoietin-2 protein was consistently upregulated more than 30-fold in the retinae of diabetic rats, preceding the onset of pericyte loss. Heterozygous angiopoietin-2 deficiency completely prevented diabetes-induced pericyte loss and reduced the number of acellular capillary segments. Injection of angiopoietin-2 into the eyes of normal rats induced a dose-dependent pericyte loss. These data show that upregulation of angiopoietin-2 plays a critical role in the loss of pericytes in the diabetic retina.
周细胞丢失是糖尿病视网膜病变的早期病理特征，在糖尿病患者和动物的视网膜中持续存在。由于周细胞募集和内皮细胞存活部分受血管生成素/Tie2配体/受体系统控制，我们使用定量视网膜形态学方法，研究了血管生成素-2和-1的表达与糖尿病大鼠视网膜周细胞丢失演变的关系，并在血管生成素杂合缺陷小鼠（Ang-2 LacZ敲入小鼠）的视网膜中进行了研究。最后，将重组血管生成素-2注入非糖尿病大鼠眼中，并对视网膜毛细血管中的周细胞数量进行定量。血管生成素-1蛋白存在于正常成熟视网膜中，在糖尿病视网膜中，随着糖尿病病程3个月的进展，其表达上调2.5倍。相比之下，在周细胞丢失开始之前，血管生成素-2蛋白在糖尿病大鼠视网膜中持续上调超过30倍。血管生成素-2杂合缺陷完全阻止了糖尿病诱导的周细胞丢失，并减少了无细胞毛细血管段的数量。向正常大鼠眼中注射血管生成素-2会导致剂量依赖性的周细胞丢失。这些数据表明，血管生成素-2的上调在糖尿病视网膜周细胞丢失中起关键作用。
