Orexin B Reduces Cerebral Aneurysms Through Inhibition of SP-1
Lei Chen1, Jinlong Xu1, Fengyun Ye1
1Department of Neurosurgery, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China.
Background:
Cerebral aneurysms (CAs) are pathological dilations of intracranial arteries with high rupture risk, yet the molecular mechanisms driving their formation remain incompletely understood. The Orexin B/OX2R system, known for regulating arousal and metabolism, has recently been implicated in vascular pathology, but its role in CAs has not been explored.
Methods:
Serum Orexin A and B levels were measured in 38 CA patients and 43 healthy controls. A murine CA model (elastase-induced) was established using wild-type (WT) and OX2R knockout (OX2R-/-) mice, with or without Orexin B treatment (30 μg/kg/day for 7 weeks). Aneurysm size, inflammatory mediators (IL-6, MMP-9, MCP-1, E-selectin), macrophage infiltration (CD68), and SP-1 expression were assessed. In vitro studies using human brain microvascular endothelial cells (HBMVECs) examined Ang II-induced OX2R suppression, monocyte adhesion, and SP-1-mediated signaling following Orexin B treatment and SP-1 overexpression.
Results:
CA patients and mice exhibited significantly reduced serum Orexin B levels (CA patients: 3.21 ± 0.52 vs. controls: 8.56 ± 1.23 pg/mL, p < 0.01), with no change in Orexin A. OX2R expression was downregulated in the circle of Willis of CA mice. Orexin B administration attenuated aneurysm formation in WT mice (size reduction from 3.72 ± 0.469 mm to 1.93 ± 0.252 mm, p < 0.01) but not in OX2R-/- mice. Orexin B suppressed IL-6, MMP-9, MCP-1, and E-selectin expression, reduced CD68+ macrophage infiltration, and decreased SP-1 levels in WT but not OX2R-/- mice. In HBMVECs, Ang II dose-dependently reduced OX2R expression. Orexin B inhibited Ang II-induced monocyte adhesion and SP-1-mediated pro-inflammatory signaling, effects abolished by OX2R siRNA or SP-1 overexpression.
Conclusions:
The Orexin B/OX2R axis is dysregulated in CAs, and Orexin B protects against CA formation through OX2R-dependent anti-inflammatory mechanisms involving SP-1 suppression. These findings identify the Orexin B/OX2R/SP-1 pathway as a potential therapeutic target for cerebral aneurysms.