Endogenous Renovascular Hypertension Combined With Low Shear Stress Induces Plaque Rupture in Apolipoprotein E–Deficient Mice

Abstract

Objective-The development of a murine model of spontaneous atherosclerotic plaque rupture with luminal thrombus. Methods and Results-Combined partial ligation of the left renal artery and left common carotid artery in 8-week-old apolipoprotein E-deficient mice induced endogenous renovascular hypertension and local low oscillatory shear stress in the left common carotid artery. After 8 weeks, a fresh left common carotid artery lumen thrombus associated with severe plaque burden was found in 50% (10/20) of the mice. Histological analyses indicated that all left common carotid artery lesions had vulnerable features, and 50% (5/10) of the mice showed plaque rupture with a lumen thrombus. Multiple layers with layering discontinuity and intraplaque hemorrhages were found in 80% (8/10) of the mice. Further experiments showed that both increased blood pressure, and angiotensin-II contributed to plaque progression and vulnerability. Decreased intimal collagen associated with increased collagenase activity and matrix metalloproteinase expression also resulted in plaque disruption. Conclusion-We demonstrate a murine model of spontaneous plaque rupture with a high incidence of luminal thrombus.The model not only nicely recapitulates the pathophysiological processes of human plaque rupture but it is also simple, fast, and highly efficient to generate. Therefore, in this study, using the method of partial ligation of left carotid and left renal arteries, we induced local stress change, as well as continuously activated reninangiotensin system in ApoE knockout mice. High incidence of spontaneous plaque rupture associated with lumen thrombosis was successfully generated by combining systematic and local factors. Furthermore, this simple murine model not only nicely recapitulates the pathophysiological processes of human plaque rupture but also has rapid plaque progression. Materials and Methods MiceApoE-deficient (ApoE −/− ) mice on a C57BL/6 background were obtained from the Jackson Laboratory (Bar Harbor, ME). Age-(8-week-old) and sex-matched animals weighing between 20 and 25 g were enrolled in the study. Mice batch 1 was randomly assigned to 5 groups: combined partial ligation of left renal artery and left common carotid artery (LCCA) (R+C), partial ligation of left renal artery (R), partial ligation of LCCA (C), sham control (S), and open control (O). Mice batch 2 was also randomly assigned to 5 groups: combined partial ligation of left renal artery and LCCA + intragastrically administered normal saline (R+C+NS), combined partial ligation of left renal artery and LCCA + intragastrically administered losartan (R+C+LO), partial ligation of LCCA + subcutaneous normal saline infusion (C+NS), partial ligation of LCCA + subcutaneous angiotensin II infusion (C+ANG), and partial ligation of LCCA + subcutaneous phenylephrine infusion (C+PHE). For time series experiment, mice were randomly assigned to 4 groups: sham operation was performed in mice of group 1; mice of other groups underwent partial ligation both of LCCA and left ren...

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability

“…Unstable carotid atherosclerotic lesions were induced by combined partial ligation of the left renal artery and left internal and external carotid artery with perivascular collars. 18 Six weeks after surgery, all mice were randomly assigned to either an interventional or a control group. Mice in the interventional group were treated with daily subcutaneous injection of TRAM-34 (120 mg/kg) for 3 weeks, whereas mice in the control group were injected with vehicle (Miglyol 812).…”

Atherosclerotic Plaque Destabilization

“…70 A combination of blood flow shear modification and hypertension induced by partial ligation of the renal artery had similar effects. 71 Recently, a model of vulnerable plaque formation based on the induction of a tandem stenosis was proposed. 72 In this model, a high incidence of plaque disruption and intraplaque hemorrhage was observed.…”

Atherosclerotic Plaque Rupture

“…[50][51][52] Recently, several animal models have been designed based on the concept discussed above to create low shear stress and high tensile stress. Jin et al 53 describe a ligation and hypertension-induced model of plaque rupture. ApoE −/− mice were subjected to partial ligations of the left renal and common carotid arteries.…”

“…Also, in 50% of these mice, there was evidence of intraluminal thrombosis. 53 Chen et al 47 used a tandem stenosis in the common carotid artery of ApoE −/− mice to create a defined area that is exposed to low shear stress and high tensile stress. This model reflects human plaque instability, including the presence of ruptured thin fibrous caps, accumulation of lipids with large necrotic cores, intraplaque hemorrhage, intraluminal thrombosis, and strong inflammatory cell infiltration.…”