Department of Ophthalmology, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark.
Exp Eye Res. 2013 Oct;115:79-86. doi: 10.1016/j.exer.2013.06.013. Epub 2013 Jun 24.
Metabolic disturbances in diabetes mellitus include changes in the type and concentration of lipids in the blood plasma which may contribute to the development of diabetic retinopathy. This disease is characterized by changes in retinal blood flow secondary to changes in the tone of retinal arterioles which is regulated by compounds such as adenosine, adenosine triphosphate (ATP), the glutamate agonist N-methyl-d-aspartate (NMDA) and prostaglandin E2 (PGE2). However, the relation between increased plasma low density lipoprotein (LDL) and tone regulation in retinal resistance vessels has not been studied in detail. Twelve male and nine female Yucatan minipigs overexpressing a gain-of-function mutant (D374Y) of the human gene PCSK9 that blocks LDL transport into the liver and twelve wild-type males were studied. The animals were fed a cholesterol rich diet from the age of 60 days, followed by induction of diabetes mellitus in twelve of the transgenic animals. The animals were sacrificed at a mean age of 51 weeks (range 26-60 weeks), followed by inspection and histological examination of retinal vessels, and examination of the changes in vascular tone induced by adenosine, ATP, NMDA and PGE2. In the transgenic pigs without diabetes mellitus ATP-induced relaxation was reduced in isolated arterioles, and a whitish infiltration in an arteriole was observed in 4/8 (50%) of the animals, whereas these changes were not found in the other groups. Histological examination of one of the infiltrations showed staining with Oil Red O representing foamy cells sub-endothelially in the vascular wall indicating atheromatosis. Adenosine, ATP and PGE2 induced a significant concentration-dependent relaxation of retinal arterioles in all groups. The presence of perivascular retinal tissue had no effect on the relaxing effect of adenosine, but increased the relaxing effect of ATP and PGE2 in the two transgenic animal groups, whereas NMDA had no significant effect on vascular tone in any of the groups. Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL-receptor deficiency and diabetes mellitus. This suggests that transgenic animal models are suitable for studying the influence of systemic diseases on retinal vascular function.
糖尿病患者的代谢紊乱包括血浆中脂质的类型和浓度变化，这可能导致糖尿病性视网膜病变的发生。这种疾病的特征是视网膜血流的变化，这是由于视网膜小动脉张力的变化引起的，而视网膜小动脉张力是由化合物如腺苷、三磷酸腺苷 (ATP)、谷氨酸激动剂 N-甲基-D-天冬氨酸 (NMDA) 和前列腺素 E2 (PGE2) 调节的。然而，血浆中低密度脂蛋白 (LDL) 增加与视网膜阻力血管张力调节之间的关系尚未得到详细研究。研究了 12 只雄性和 9 只雌性 Yucatan 小型猪，它们过表达一种能阻止 LDL 进入肝脏的人 PCSK9 基因的功能获得性突变 (D374Y)，以及 12 只野生型雄性猪。这些动物从 60 天大时开始喂食富含胆固醇的饮食，然后在 12 只转基因动物中诱导糖尿病。这些动物在平均 51 周龄（26-60 周龄）时被处死，然后检查和组织学检查视网膜血管，并检查腺苷、ATP、NMDA 和 PGE2 诱导的血管张力变化。在没有糖尿病的转基因猪中，分离的小动脉中 ATP 诱导的舒张作用减弱，并且在 8/8（50%）的动物中观察到一条小动脉的灰白色浸润，而在其他组中未发现这些变化。对其中一个浸润的组织学检查显示用油红 O 染色，代表血管壁内皮下的泡沫细胞，表明动脉粥样硬化。在所有组中，腺苷、ATP 和 PGE2 都能显著地浓度依赖性地舒张视网膜小动脉。视网膜周围组织的存在对腺苷的舒张作用没有影响，但增加了在两个转基因动物组中 ATP 和 PGE2 的舒张作用，而 NMDA 在任何一组中对血管张力都没有显著影响。体内暴露于高胆固醇血症的猪视网膜小动脉的舒张作用受肝脏 LDL 受体缺乏和糖尿病的影响。这表明转基因动物模型适合研究全身疾病对视网膜血管功能的影响。
