Atherosclerotic Plaque Destabilization in Mice: A Comparative Study

Abstract

Atherosclerosis-associated diseases are the main cause of mortality and morbidity in western societies. The progression of atherosclerosis is a dynamic process evolving from early to advanced lesions that may become rupture-prone vulnerable plaques. Acute coronary syndromes are the clinical manifestation of life-threatening thrombotic events associated with high-risk vulnerable plaques. Hyperlipidemic mouse models have been extensively used in studying the mechanisms controlling initiation and progression of atherosclerosis. However, the understanding of mechanisms leading to atherosclerotic plaque destabilization has been hampered by the lack of proper animal models mimicking this process. Although various mouse models generate atherosclerotic plaques with histological features of human advanced lesions, a consensus model to study atherosclerotic plaque destabilization is still lacking. Hence, we studied the degree and features of plaque vulnerability in different mouse models of atherosclerotic plaque destabilization and find that the model based on the placement of a shear stress modifier in combination with hypercholesterolemia represent with high incidence the most human like lesions compared to the other models.

Fig 1. Schematic diagrams and experimental setups of the mouse models of atherosclerotic plaque destabilization.

(A) Model based on the combined partial ligation of LCCA (left) and LRA (right). (B) Model based on the combination of cast placement around LCCA (left) and partial ligation of LRA (right). (C) Model based on the partial ligation of LCCA in combination with the cast placement around the LCCA. (D) Model based on cast placement around the LCCA. LCCA: left common carotid artery; LRA: left renal artery; LECA: left external carotid artery; LICA: left internal carotid artery; LSTA: left superior thyroid artery; CD: chow diet; HFD: high fat diet; Lig.: ligation.

Fig 2. Representative carotid cross-sections of studied specimens for the mouse models of atherosclerotic plaque destabilization.

Mice were fed chow diet (CD) or high fat diet (HFD) as indicated. From left to right: LCCA LRA, model based on the combination of partial ligation of LCCA and LRA; LRA Cast, model based on the combined cast placement around LCCA and partial ligation of LRA; LCCA Cast, model based on the partial ligation of LCCA in combination with the cast placement around the LCCA; Cast, model based on cast placement around the LCCA. Red, yellow and green bars represent thrombus, no lesion or atherosclerotic lesion, respectively. Scale bar = 100μm. LCCA: left common carotid artery; LRA: left renal artery; CD: chow diet; HFD: high fat diet.

Fig 3. Structural features of the atherosclerotic lesions.

Quantification of (A) intimal area, (B) intima to media ratio, (C) necrotic core size and (D) fibrous cap thickness. Fibrous cap thickness was only measured when necrotic core was present. NC: necrotic core; FC: fibrous cap; CD: chow diet; HFD: high fat diet; LCCA: left common coronary artery; LRA: left renal artery.

Fig 4. Compositional features of the atherosclerotic lesions.

Quantification of (A) macrophage (CD68+ area), (B) vascular smooth muscle cell (SMA+ area) and (C) total collagen (picrosirius red+ area) content. (D) Quantification of the incidence of intraplaque hemorrhage in Pearls’ Prussian blue stained sections. CD: chow diet; HFD: high fat diet; LCCA: left common coronary artery; LRA: left renal artery; IPH: intraplaque hemorrhages.