Modified Intracranial Aneurysm Rupture Rat Model with Angiographic Imaging

Abstract

Intracranial aneurysms (IAs) are a major cause of spontaneous subarachnoid hemorrhage (SAH) and are associated with high morbidity and mortality. Current IA rodent models often exhibit low rupture rates and limited imaging capabilities, restricting their translational utility. This study introduces a modified elastase-based rat model that incorporates angiographic imaging to overcome these challenges. IAs were induced in 7-week-old female Sprague-Dawley rats using a combination of surgical and pharmacological interventions, including carotid artery and renal artery ligation, bilateral ovariectomy, high-salt diet, and two elastase injections into the basal cistern. Digital subtraction angiography (DSA) was employed to assess aneurysm formation and rupture rate. Histological and immunohistochemical analyses were conducted to characterize aneurysm morphology and the inflammatory response. The modified model achieved a high rate of IA formation (85%) and rupture (60%) within 28 days. DSA enabled visualization of vessel tortuosity and flow dynamics, features relevant to human IA development, which often occurs in areas subjected to hemodynamic stress, and the tortuosity of intracranial vessels affects their rupture ^[1]. Histological analysis indicated structural degradation of the aneurysm wall, while immunohistochemistry showed neutrophil infiltration, potentially implicating inflammation in IA rupture. This improved IA model offers a reliable method for inducing and visualizing IAs with a high rupture rate, making it a valuable tool for studying the pathophysiology and therapeutic interventions of IAs. Enhanced by DSA, this model has the potential to advance therapeutic research by enabling the real-time monitoring of aneurysm development and rupture.

Keywords: Digital subtraction angiography; Hemodynamic force; Intracranial aneurysms; Rat model; Subarachnoid hemorrhage.

Fig. 1

The vessel flows after establishing the model. A The anatomy of the intracranial vessels. B Digital subtraction images of the intracranial vessel immediately after establishing the model. The images in the upper line represent the anterior circulation and the images in the lower lines represent the posterior circulation. C A schematic of the blood flow. Abbreviation: ACA, anterior cerebral artery; BA, basilar artery; ICA, internal cerebral artery; PCA, posterior cerebral artery; Pcom, posterior communicating artery; PPA, pterygopalatine artery; VA, vertebral artery

Fig. 2

Number and anatomical distribution of unruptured and ruptured IAs. The animals were maintained for 4 weeks after establishing the model or autopsied if they died during the observation period. The upper panel shows the number and location of the unruptured IAs. The lower panel shows the number and location of the ruptured IAs. Abbreviation: ACA, anterior cerebral artery; BA, basilar artery; ICA, internal cerebral artery; PCA, posterior cerebral artery; Pcom, posterior communicating artery; PPA, pterygopalatine artery; VA, vertebral artery

Fig. 3

The comparison of blood vessels in this model and a healthy rat. The animals were maintained for 4 weeks after establishing the model or autopsied if they died during the observation period. The upper panels show the right anterior circulation in this model (right panel) and in healthy rats (left panel). The lower figures show the posterior circulation of this model (right panel) and healthy rats (left panel). Abbreviation: ACA, anterior cerebral artery; BA, basilar artery; ICA, internal cerebral artery; PCA, posterior cerebral artery; Pcom, posterior communicating artery; PPA, pterygopalatine artery; VA, vertebral artery

Fig. 4

Histological and immunohistochemical analysis of ruptured intracranial aneurysms. The upper lines show images of Elastica van Gieson staining of the ruptured IA (right panel). This image shows the lack of elastic lamina in the aneurysmal wall and inflammatory cells infiltrating the wall. Scale bar; 50 µm. In the lower panel, immunohistochemical images show that these inflammatory cells were myeloperoxidase-positive and appeared to infiltrate the vasa vasorum. Scale bar; 50 µm. Abbreviation: SMA, smooth muscle actin; MPO, myeloperoxidase