Pathological Investigations of Intracranial Atherosclerosis Using Multiple Hypercholesterolemic Rabbit Models

Abstract

BackgroundIntracranial atherosclerosis (ICAS) is one of the most common causes of ischemic stroke, but there are few animal models that can recapitulate its pathological features. In this study, we examined ICAS pathological features and anatomic distributions using three types of hyperlipidemic rabbit models. We also investigated the effect of different lipoprotein profiles and hypertension on ICAS.Materials and MethodsWe examined Watanabe heritable hyperlipidemic (WHHL) rabbits, apoE knockout (KO) rabbits and wild-type rabbits (WT) fed a cholesterol diet, in addition to WT rabbits fed a standard diet as a control. The whole brain was dissected and embedded in paraffin. Serial sections were stained with either hematoxylin/eosin or elastica van Gieson, or immunohistochemically stained with monoclonal antibodies against macrophages and smooth muscle cells. We investigated (1) the presence of cerebral atherosclerosis; (2) the lesion locations in the cerebral arteries; (3) the degree of lumen stenosis; (4) pathological features and cellular components of the lesions in these rabbits; and (5) whether hypertension affects ICAS.ResultsICAS was detected in apoE and WHHL rabbits, but not in WT rabbits. Compared with apoE KO rabbits, WHHL rabbits had greater ICAS. The lesions of cerebral atherosclerosis were mainly distributed at the bifurcations of the posterior cerebral artery, basilar artery and vertebral artery, and they were basically characterized by smooth muscle cells and extracellular matrix with few macrophages. The extent of the ICAS in WHHL rabbits was significantly increased by hypertension.ConclusionsICAS was detected in WHHL and apoE KO rabbits, and occurred in specific locations in the cerebral arteries. Hypertension promotes the development of ICAS in the setting of hypercholesterolemia.

Enhanced atherosclerosis in apolipoprotein E knockout rabbits: role of apoB48-rich remnant lipoproteins

“…Different types of hyperlipidemia may have different arterial preferences for atherosclerosis. Intracranial atherosclerosis of apoE KO rabbits was reported in previous studies ( 37 , 38 ). Intracranial atherosclerosis was developed in apoE rabbits fed a CRD but WHHL rabbits, a model for human FH, exhibited more severe lesions than apoE KO rabbits.…”

Recent Translational Research Models of Intracranial Atherosclerotic Disease

“…However, a notable caveat in this study is that most ApoE-KO rabbits were fed an atherogenic diet. 34 By contrast, a subsequent study by Tang et al 32 evaluated differences between WHHL and ApoE-KO rabbits and found that WHHL animals develop more severe ICAD than ApoE-KO animals. This study further demonstrated that the induction of hypertension exacerbates ICAD in WHHL animals.…”

“…This study further demonstrated that the induction of hypertension exacerbates ICAD in WHHL animals. 32 The Tang group identified smooth muscle cells and infiltrating macrophages as the major components of the atherosclerotic lesions in both models, and they observed that lesions occurred mainly at bifurcations of the posterior cerebral artery, basilar artery, and vertebral artery. 32 While these rabbit models show evidence of lesions in a wider variety of intracranial arteries than other small animal models, they do not seem to recapitulate ICAD in more distal arteries like the ICA and MCA, which are often affected in human patients.…”