慢性社会挫败应激导致视网膜血管功能障碍。

Chronic social defeat stress causes retinal vascular dysfunction.

机构信息

Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany; Department of Ophthalmology, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

Johannes Gutenberg University Medical Center, Mainz, Germany.

出版信息

Exp Eye Res. 2021 Dec;213:108853. doi: 10.1016/j.exer.2021.108853. Epub 2021 Nov 18.

DOI:10.1016/j.exer.2021.108853

PMID:34800481

Abstract

PURPOSE

The roles of vascular dysfunction and chronic stress have been extensively discussed in the pathophysiology of glaucoma. Our aim was to test whether chronic stress causes retinal vascular dysfunction and therewith induces retinal ganglion cells (RGCs) loss.

METHODS

Twelve mice underwent chronic social defeat (CSD) stress, while 12 mice received control treatment only. Intraocular pressure (IOP) was measured with a rebound tonometer. Blood plasma corticosterone concentration and adrenal gland weight were used to assess stress levels. Brn-3a staining in retinas and PPD staining in optic nerve cross sections were conducted to assess the survival of RGCs and axons respectively. The ET-1 and α-SMA levels were determined in retina. Retinal vascular autoregulation, functional response to various vasoactive agents and vascular mechanics were measured using video microscopy.

RESULTS

No significant difference in IOP levels was observed during and after CSD between CSD mice and controls. CSD stress caused hypercortisolemia 2 days post-CSD. However, increased corticosterone levels went back to normal 8 months after CSD. CSD-exposed mice developed adrenal hyperplasia 3 days post-CSD, which was normalized by 8 months. RGC and axon survival were similar between CSD mice and controls. However, CSD stress caused irreversible, impaired autoregulation and vascular dysfunction of retinal arterioles in CSD mice. In addition, impaired maximal dilator capacity of retinal arterioles was observed 8 months post-CSD rather than 3 days post-CSD. Remarkably, ET-1 levels were increased 3 days post-CSD while α-SMA levels were decreased 8 months post-CSD.

CONCLUSIONS

We found that CSD stress does not cause IOP elevation, nor loss of RGCs and their axons. However, it strikingly causes irreversible impaired autoregulation and endothelial function in murine retinal arterioles. In addition, CSD changed vascular mechanics on a long-term basis. Increased ET-1 levels and loss of pericytes in retina vessels may involve in this process.

摘要

目的

血管功能障碍和慢性应激在青光眼的病理生理学中已经得到了广泛的讨论。我们的目的是测试慢性应激是否会导致视网膜血管功能障碍，并由此导致视网膜神经节细胞（RGC）的损失。

方法

12 只小鼠接受慢性社会挫败（CSD）应激，而 12 只小鼠仅接受对照处理。使用回弹眼压计测量眼内压（IOP）。血浆皮质酮浓度和肾上腺重量用于评估应激水平。Brn-3a 染色在视网膜中进行，PPD 染色在视神经横切面上进行，分别评估 RGC 和轴突的存活情况。在视网膜中测定 ET-1 和 α-SMA 水平。使用视频显微镜测量视网膜血管自动调节、对各种血管活性物质的功能反应和血管力学。

结果

CSD 小鼠和对照组在 CSD 期间和之后的 IOP 水平没有显著差异。CSD 应激导致 CSD 后 2 天皮质酮升高。然而，8 个月后，皮质酮水平恢复正常。CSD 暴露的小鼠在 CSD 后 3 天发生肾上腺增生，8 个月后恢复正常。RGC 和轴突的存活在 CSD 小鼠和对照组之间相似。然而，CSD 应激导致 CSD 小鼠的视网膜小动脉自动调节和血管功能不可逆受损。此外，在 CSD 后 8 个月而非 CSD 后 3 天观察到视网膜小动脉最大扩张能力受损。值得注意的是，CSD 后 3 天 ET-1 水平升高，而 CSD 后 8 个月 α-SMA 水平降低。