Yu Huimin, Xie Minghong, Liufu Xuancong, Xu Yezi, Chen Lei
Department of Neurology, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, Guangdong Province, China.
Department of Neurosurgery, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, Guangdong Province, China.
CNS Neurosci Ther. 2025 May;31(5):e70413. doi: 10.1111/cns.70413.
Cerebral aneurysms (CAs) are a prevalent brain condition with poorly understood pathological features. The Kisspeptin-10 (KP-10)/G protein-coupled receptor 54 (GPR54) system is a vital neuroendocrine pathway primarily implicated in the regulation of reproductive functions and energy metabolism. This research explores the role of the KP-10/GPR54 system in CAs.
Serum levels of KP-10 in CA patients and animal models were assessed using commercial ELISA kits. Mice were divided into five groups: WT, GPR54, CA, CA + KP-10, and CA + GPR54 + KP-10. The CA profiles were evaluated using Verhoeff-van Gieson staining. Human brain microvascular endothelial cells (HBMVECs) were stimulated with Ang II (10 mol/L) with or without KP-10 (50, 100 nM). Angiogenic tube formation was then assessed.
We found that KP-10 levels were reduced in both CA patients and mouse models. In CA mice, Gpr54 expression in the Circle of Willis (COW) was also decreased. KP-10 reduced CA size in wild-type mice, but not in Gpr54 knockout mice. It also reduced matrix metalloproteinase-9 (MMP-9), macrophage infiltration, and vascular endothelial growth factor-A (VEGF-A) expression, effects that were absent in Gpr54 knockout mice. In vitro, KP-10 inhibited Ang II-induced proliferation, angiogenic tube formation, and VEGF-A expression in HBMVECs by reducing early growth response-1 (Egr-1). These effects were abolished when Gpr54 was knocked down, indicating that KP-10's action is dependent on Gpr54.
This study shows that KP-10 binding to Gpr54 inhibits Egr-1 expression, thereby suppressing MMP-9 and VEGF-A, reducing macrophage infiltration and angiogenesis, and preventing cerebral aneurysm development. Thus, the KP-10/Gpr54 system is a key therapeutic target for the treatment of cerebral aneurysms.
脑动脉瘤（CAs）是一种常见的脑部疾病，其病理特征尚不清楚。 kisspeptin - 10（KP - 10）/G蛋白偶联受体54（GPR54）系统是一条重要的神经内分泌途径，主要参与生殖功能和能量代谢的调节。本研究探讨KP - 10/GPR54系统在脑动脉瘤中的作用。
使用商用ELISA试剂盒评估脑动脉瘤患者和动物模型中KP - 10的血清水平。将小鼠分为五组：野生型（WT）、GPR54基因敲除型、脑动脉瘤模型组、脑动脉瘤模型+KP - 10组和脑动脉瘤模型+GPR54基因敲除+KP - 10组。使用Verhoeff - van Gieson染色评估脑动脉瘤情况。用人血管紧张素II（Ang II，10 μmol/L）刺激人脑微血管内皮细胞（HBMVECs），同时或不同时添加KP - 10（50、100 nM），然后评估血管生成管形成情况。
我们发现脑动脉瘤患者和小鼠模型中KP - 10水平均降低。在脑动脉瘤小鼠中， Willis环（COW）中的Gpr54表达也降低。KP - 10可减小野生型小鼠的脑动脉瘤大小，但对Gpr54基因敲除小鼠无效。它还可降低基质金属蛋白酶 - 9（MMP - 9）、巨噬细胞浸润以及血管内皮生长因子 - A（VEGF - A）的表达，而这些作用在Gpr54基因敲除小鼠中不存在。在体外，KP - 10通过降低早期生长反应因子 - 1（Egr - 1）抑制Ang II诱导的HBMVECs增殖、血管生成管形成以及VEGF - A表达。当Gpr54基因敲低时，这些作用消失，表明KP - 10的作用依赖于Gpr54。
本研究表明，KP - 10与Gpr54结合可抑制Egr - 1表达，从而抑制MMP - 9和VEGF - A，减少巨噬细胞浸润和血管生成，预防脑动脉瘤发展。因此，KP - 10/Gpr54系统是治疗脑动脉瘤的关键治疗靶点。
