GLP-1 受体硝化导致糖尿病小鼠模型中脑周细胞功能丧失。
GLP-1 receptor nitration contributes to loss of brain pericyte function in a mouse model of diabetes.
机构信息
Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, South University, Savannah, GA, USA.
出版信息
Diabetologia. 2022 Sep;65(9):1541-1554. doi: 10.1007/s00125-022-05730-5. Epub 2022 Jun 10.
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.
目的/假设：我们之前已经表明，糖尿病会导致周细胞功能障碍，导致血管完整性丧失和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 RAs）用于治疗 2 型糖尿病，除了血糖控制外，还能改善糖尿病患者的认知功能，但机制尚不完全清楚。在本研究中，我们假设 GLP-1 RAs 通过防止糖尿病引起的周细胞功能障碍来改善 VCID。
方法
链脲佐菌素诱导糖尿病小鼠和非糖尿病对照小鼠通过渗透泵在 28 天内接受生理盐水（NaCl 154 mmol/l）或 exendin-4（一种 GLP-1 RA）。通过测量脑血管新生指数（血管密度、迂曲度和分支密度）评估血管完整性。使用 Barnes 迷宫和 Morris 水迷宫评估认知功能。将人脑微血管周细胞（HBMPCs）在高葡萄糖（25 mmol/l）和棕榈酸（200 μmol/l）中培养以模拟糖尿病条件。用/不用 exendin-4 处理 HBMPCs，并评估其硝化和氧化应激以及血管生成和血脑屏障功能。
结果
用 exendin-4 治疗的糖尿病小鼠所有脑病理性新生血管指数均显著降低，血脑屏障明显改善（p<0.05）。与对照组小鼠相比，糖尿病小鼠的学习和记忆功能也显著改善（p<0.05）。我们的结果表明，HBMPCs 表达 GLP-1 受体。糖尿病增加了 HBMPCs 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 HBMPCs 可降低糖尿病引起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表明，脑周细胞表达 GLP-1 受体，该受体在糖尿病条件下被硝化。GLP-1 受体激活可改善脑周细胞功能，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 可减轻小鼠糖尿病引起的认知障碍。在糖尿病中恢复周细胞功能代表了治疗糖尿病引起的脑血管微血管病变和 VCID 的新治疗靶点。
Zotero 插件