低氧诱导因子-1α 对糖尿病视网膜病变血管生成和血管内皮生长因子表达的影响。

Effects of HIF-1α on diabetic retinopathy angiogenesis and VEGF expression.

机构信息

Department of Ophthalmology, Liaocheng People's Hospital, Liaocheng, Shandong, China.

出版信息

Eur Rev Med Pharmacol Sci. 2018 Aug;22(16):5071-5076. doi: 10.26355/eurrev_201808_15699.

DOI:10.26355/eurrev_201808_15699

PMID:30178824

Abstract

OBJECTIVE

To investigate the effect of hypoxia inducing factor (HIF)-1α on the expression of vascular endothelial growth factor (VEGF) and angiogenesis in diabetic retinopathy.

PATIENTS AND METHODS

8-week healthy SD rats were used for the experiments. Under systemic anesthesia condition, control rats received a saline injection into the left ocular body (control A group), and 2 μl antisense oligonucleotides (ASODN) (10 μmol/L) into right eye (control B group). Model rats received a saline injection into the left eye (model A group), and 2 μl ASODN (10 μmol/L) into the right eye (model B group). Rats received an intraocular injection of HIF-1α ASODN for 2, 4, and 6 weeks (A1, A2, A3, B1, B2, B3, respectively). Retinal vessel development was observed by ADP staining. Vascular endothelial cells penetrating retinal inner membrane were counted. Immunohistochemistry was used to detect expressions of VEGF and HIF-1α proteins in the retina.

RESULTS

Prominent angiogenesis and hyperplasia were found in model A group. Relatively fewer newly formed vessels were shown in model group B. However, no significant change of retinal vascular morphology was presented in control group. Of note, the vascular endothelial cell counts, VEGF and HIF-1α contents were significantly increased in model group (p < 0.05). After treatment with HIF-1α ASODN, lower endothelial cell counts was found in model B group (p < 0.05 comparing to model A). VEGF expression in model B group was significantly decreased, among which, model B3 was observed with lower cell counts than model B1 or B2 (p < 0.05 comparing to model A). Injection of HIF-1α ASODN significantly suppressed HIF-1α level in model B in a time-dependent manner.

CONCLUSIONS

Retinal angiogenesis is closely related with increasing level of HIF-1α. Inhibition of HIF-1α suppressed VEGF expression and deterred angiogenesis in a time-dependent manner. This provided novel insights for treating diabetic retinopathy.

摘要

目的

探讨低氧诱导因子-1α（HIF-1α）对糖尿病视网膜病变中血管内皮生长因子（VEGF）表达和血管生成的影响。

方法

选用 8 周龄健康 SD 大鼠进行实验。全身麻醉下，对照组大鼠左眼玻璃体内注射生理盐水（对照 A 组），右眼玻璃体内注射反义寡核苷酸（ASODN）（10μmol/L）（对照 B 组）；模型组大鼠左眼玻璃体内注射生理盐水（模型 A 组），右眼玻璃体内注射 ASODN（10μmol/L）（模型 B 组）。HIF-1α ASODN 玻璃体腔内注射 2、4、6 周（A1、A2、A3、B1、B2、B3 组）。ADP 染色观察视网膜血管发育情况，计数穿透视网膜内界膜的血管内皮细胞，免疫组化法检测视网膜中 VEGF 和 HIF-1α 蛋白的表达。

结果

模型 A 组可见明显的血管生成和增生，模型 B 组新生血管较少，但对照组视网膜血管形态无明显变化。模型组血管内皮细胞计数、VEGF 和 HIF-1α 含量明显增加（p<0.05）。HIF-1α ASODN 处理后，模型 B 组血管内皮细胞计数降低（p<0.05 与模型 A 组比较），VEGF 表达降低，其中模型 B3 组细胞计数低于模型 B1 或 B2 组（p<0.05 与模型 A 组比较）。模型 B 组 HIF-1α 水平随时间呈下降趋势，呈时间依赖性。