Researchers found that a short protein called kisspeptin-10 (KP-10) can stop brain aneurysms from growing in mice. It works by attaching to a receptor (GPR54) and lowering a gene called Egr-1, which then reduces harmful enzymes and new blood‑vessel growth that normally help aneurysms form. The effect disappears if the receptor is missing, showing the pathway is essential.

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^-7 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.