Aims/hypothesis

We have previously shown that diabetes causes pericyte dysfunction, leading to loss of vascular integrity and vascular cognitive impairment and dementia (VCID). Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), used in managing type 2 diabetes mellitus, improve the cognitive function of diabetic individuals beyond glycaemic control, yet the mechanism is not fully understood. In the present study, we hypothesise that GLP-1 RAs improve VCID by preventing diabetes-induced pericyte dysfunction.

Methods

Mice with streptozotocin-induced diabetes and non-diabetic control mice received either saline (NaCl 154 mmol/l) or exendin-4, a GLP-1 RA, through an osmotic pump over 28 days. Vascular integrity was assessed by measuring cerebrovascular neovascularisation indices (vascular density, tortuosity and branching density). Cognitive function was evaluated with Barnes maze and Morris water maze. Human brain microvascular pericytes (HBMPCs), were grown in high glucose (25 mmol/l) and sodium palmitate (200 μmol/l) to mimic diabetic conditions. HBMPCs were treated with/without exendin-4 and assessed for nitrative and oxidative stress, and angiogenic and blood–brain barrier functions.

Results

Diabetic mice treated with exendin-4 showed a significant reduction in all cerebral pathological neovascularisation indices and an improved blood–brain barrier (p<0.05). The vascular protective effects were accompanied by significant improvement in the learning and memory functions of diabetic mice compared with control mice (p<0.05). Our results showed that HBMPCs expressed the GLP-1 receptor. Diabetes increased GLP-1 receptor expression and receptor nitration in HBMPCs. Stimulation of HBMPCs with exendin-4 under diabetic conditions decreased diabetes-induced vascular inflammation and oxidative stress, and restored pericyte function (p<0.05).

Conclusions/interpretation

This study provides novel evidence that brain pericytes express the GLP-1 receptor, which is nitrated under diabetic conditions. GLP-1 receptor activation improves brain pericyte function resulting in restoration of vascular integrity and BBB functions in diabetes. Furthermore, the GLP-1 RA exendin-4 alleviates diabetes-induced cognitive impairment in mice. Restoration of pericyte function in diabetes represents a novel therapeutic target for diabetes-induced cerebrovascular microangiopathy and VCID.

Graphical abstract

中文翻译：

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GLP-1 受体硝化导致糖尿病小鼠模型脑周细胞功能丧失

目标/假设

我们之前已经证明，糖尿病会导致周细胞功能障碍，导致血管完整性丧失以及血管性认知障碍和痴呆（VCID）。胰高血糖素样肽-1 (GLP-1) 受体激动剂 (GLP-1 RA) 用于治疗 2 型糖尿病，可改善糖尿病患者的认知功能，使其超出血糖控制范围，但其机制尚不完全清楚。在本研究中，我们假设 GLP-1 RA 通过预防糖尿病引起的周细胞功能障碍来改善 VCID。

方法

患有链脲佐菌素诱导的糖尿病的小鼠和非糖尿病对照小鼠在 28 天内通过渗透泵接受盐水（154 mmol/l 氯化钠）或 Exendin-4（一种 GLP-1 RA）。通过测量脑血管新生血管形成指数（血管密度、迂曲度和分支密度）来评估血管完整性。采用巴恩斯迷宫和莫里斯水迷宫评估认知功能。人脑微血管周细胞 (HBMPC) 在高葡萄糖 (25 mmol/l) 和棕榈酸钠 (200 μmol/l) 中生长以模拟糖尿病状况。HBMPC 使用/不使用 Exendin-4 进行处理，并评估硝态和氧化应激、血管生成和血脑屏障功能。

结果

用 exendin-4 治疗的糖尿病小鼠显示所有脑病理性新生血管指数显着降低，血脑屏障得到改善（p <0.05）。与对照小鼠相比，糖尿病小鼠的血管保护作用伴随着学习和记忆功能的显着改善（p <0.05）。我们的结果表明 HBMPC 表达 GLP-1 受体。糖尿病增加 HBMPC 中 GLP-1 受体的表达和受体硝化。在糖尿病条件下用 exendin-4 刺激 HBMPC 可减少糖尿病诱导的血管炎症和氧化应激，并恢复周细胞功能 ( p <0.05)。

结论/解释

这项研究提供了新的证据，证明大脑周细胞表达 GLP-1 受体，该受体在糖尿病条件下会被硝化。GLP-1 受体激活可改善大脑周细胞功能，从而恢复糖尿病患者的血管完整性和 BBB 功能。此外，GLP-1 RA exendin-4 可减轻糖尿病引起的小鼠认知障碍。糖尿病中周​​细胞功能的恢复代表了糖尿病引起的脑血管微血管病和 VCID 的新治疗靶点。

图形概要