A Modified Mouse Model of Intracranial Aneurysm Based on Hemodynamic Change and Hypertension

Summary

Intracranial aneurysm (IA) was constructed in mice using the risk factors of hypertension and hemodynamic changes. Hemodynamic changes were induced by ligating branches of the carotid artery, while hypertension was achieved by ligating the posterior branches of the renal artery. IA formation was detected through magnetic resonance angiography, stereomicroscopy, and pathological analysis.

Abstract

Intracranial aneurysm (IA) poses a significant health risk due to morbidity and mortality associated with aneurysm rupture. However, the molecular mechanisms underlying IA development remain unclear, and a suitable mouse model is required. A mouse model of IA was established by ligating the pterygopalatine artery (PPA) to induce additive hemodynamic changes, combined with hypertension induction. In C57BL/6 male mice, vessels, including the right PPA, external carotid artery (ECA), occipital artery (OcA), and the left contralateral common carotid artery (CCA), were ligated to induce hemodynamic changes. One week later, the bilateral posterior branches of the renal artery (pRA) were ligated, and an 8% salt diet was introduced to induce hypertension. Magnetic resonance angiography (MRA), stereomicroscopy, and immunohistochemical (IHC) staining were performed to evaluate the morphological and pathological changes in IA three months after induction. In the experimental group, four mice died after the initial induction. IA at different locations was detected in five of the eleven remaining mice. Both microscopic and MRA examinations confirmed IA formation. Pathological and IHC analyses revealed disruption of the internal elastic lamina, disconnection of collagen fibers, and infiltration of CD86-positive M1 macrophages, findings consistent with those observed in human IA. This mouse model of IA replicates the pathological changes observed in human samples and may serve as a valuable tool for investigating the molecular mechanisms of IA formation and progression.

Introduction

The prevalence of intracranial aneurysm (IA) is estimated to be 3.2% of the general population¹. IA poses a significant health risk due to its high associated morbidity and mortality. IA is a complex and multidimensional pathological condition influenced by hemodynamic changes, inflammation, and vascular remodeling^2,3. Hemodynamic changes and hypertension are implicated in the formation and progression of aneurysms^4,5. IA frequently occurs at cerebral bifurcations with elevated hemodynamic shear stress⁶, ....

Protocol

All operational procedures in mice adhered to the criteria of the Ethical Review Committee and were approved by the Institutional Animal Care and Use Committee of Shanghai Jiaotong University. C57BL/6 male mice (8 weeks old, 20-25 g) were housed at a temperature of 22 °C with a 12 h/12 h light/dark cycle. The operational process is shown in Figure 1A. Briefly, in anesthetized animals, the left common carotid artery (CCA), right external carotid artery (ECA), occipital artery (OcA), and pterygopalatine artery (PPA) were ligated to induce hemodynamic changes. Hypertension was subsequently induced by ligating the bilateral renal arterie....

Results

Rate of IA formation
In the experimental group (n = 15), 2 mice died within the first week after the initial procedure for unknown reasons. One mouse died from an infection in the back wound on the third day after the second procedure, and another mouse died on day 38 for unknown reasons, with no aneurysms detected. In the control group (n = 5), all 5 mice survived until sacrifice. Among the surviving mice in the experimental group (n = 11), the systolic blood pressure at three months post-induction .......

Discussion

This study presents a modified approach to constructing a mouse model of IA through ligation of the PPA to induce additive hemodynamic changes in combination with hypertension. MRA imaging and microscopic analysis demonstrated significant aneurysmal changes in the circle of Willis. The pathological alterations observed in this model are consistent with those found in human samples. This mouse model may serve as a valuable tool for investigating the molecular mechanisms underlying IA formation and developme.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
7.0 T magnetic resonance angiography	Bruker	BioSpec 70/20
C57BL/6 mice	Charles River Laboratories		sex: male
CD86 antibody	CST	91882
Elastic Van Gieson (EVG)stain	Solarbio	G1597
Masson	Solarbio	G1340
Micro forcep	Shanghai Jinzhong Instrument Company
Microfil	Flow Tech Inc.	MV-120
Small animal anesthesia machine	RWD	R500
Stereo microscope	Shanghai Optical Instrument Company	XYH-6B
Suture	Shanghai Jinhuan Medical Company		6-0, 8-0