Distribution of atherosclerotic lesions in various arteries of WHHLMI rabbits, an animal model of familial hypercholesterolemia

Abstract

In WHHLMI rabbits, arterial lesions develop spontaneously in various arteries even with standard chow. Here, we examined the development of arterial lesions in various arteries to demonstrate standard characteristics of arterial lesions in WHHLMI rabbits. For WHHLMI rabbits at 6, 12, 20, and 30 months of age, lesion areas and areas of arterial lumen surfaces were measured using image analysis software. Histopathological sections of arterial lesions were stained with elastic van Gieson staining. Arterial lesions developed around bifurcations and expanded with aging. In the aorta, atheromatous lesions were severe in the thoracic aorta but were mild in the distal part of the abdominal aorta. Carotid artery lesions progressed in the proximal region and at bifurcations, and the histopathological features were similar to those of coronary lesions. Pulmonary artery lesions contained many foam cells. Fibrous lesions were observed in the proximal and distal areas of the renal arteries, at the bifurcation of the iliac-femoral artery and mesenteric artery, and around the anastomosis of vertebral arteries. Lesions in the celiac artery contained foam cells and/or lipid droplets within fibrous lesions. In a pair of right and left arteries, the arterial lesions tended to progress more in the right artery. Gender did not affect analysis of arterial lesions. In conclusion, the arterial lesions expanded from bifurcations, and the morphological features of the arterial lesions varied depending on the type of artery. These results serve as reference data for arterial lesions in studies using WHHLMI rabbits.

The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

“…Various lesions, including atheroma, are observed in carotid arteries, brachiocephalic arteries, celiac arteries, and superior mesenteric arteries. However, arterial lesions were not observed in intracranial and intravisceral small arteries 13,15) . Differences in lesion components in various arteries may depend on the differences in arterial structure, blood flow, blood pressure, and risk factors dependent on each arterial lesion.…”

“…• Accumulation of lipid-laden foam cells derived from macrophages and smooth muscle cells in atherosclerotic lesions [44][45][46][47][48] • Suppression of the development of atherosclerosis in hypercholesterolemia by inhibition of LDL oxidation 49,50) • Accumulation of peroxidized apoB-100 containing lipoproteins in atherosclerotic lesions 51) • Expression of monocyte adhesion molecules on vascular endothelial cells, and infiltration of macrophages derived from monocyte adhered into subendothelial area 52) • Expression of VLDL receptors on macrophages in atherosclerotic lesions 58) • Accumulation of lipid vesicles and cholesterol esters containing peroxidized fatty acids in the extracellular matrix 48) • Differences in the lesion components depending on the type of artery 15,61) erosclerosis may be partially different between humans and animals. In addition, macrophages in atherosclerotic lesions express VLDL receptors in humans and WHHLMI rabbits but not in mice 58) .…”

“…Therefore, it should be noted that the pathogenesis of ath- Table 3. Characteristics of coronary lesions elucidated in studies using WHHL rabbit family • Differences between coronary artery lesions rich in fibers and aortic lesions rich in lipids 15,61) • The relevance of factors other than conventional risk factors (such as serum total cholesterol levels, HDL levels, oxidative stress, hyperglycemia, hypertension, and others) in the development and progression of coronary lesions 75) • Involvement of genetic factors different from aortic lesions in the development of coronary artery lesions 75) , and involvement of the coronary curvature in the progression and composition of lesions 68) • The relevance of additional factor(s) in the rupture of unstable coronary lesions characterized by thin-capped fibroatheroma 4,22,65) • Involvement of coronary spasm in rupture of coronary lesions and the occurrence of acute coronary syndromes 22,65) • The relevance of several serum lipid molecules identified with lipidome analyses in the development and progression of coronary lesions 75) • Involvement of macrophages infiltrated into the deep area of intima through vasa vasorum 29) in coronary outward remodeling 67) • Suppression and destabilization of atherosclerotic lesions by lowering serum lipid levels 5) human coronary lesions 30) , various types of coronary lesions were observed in WHHLMI rabbits (Fig. 3), such as fatty streak, fibrous lesion, fibroatheroma, thin-capped fibroatheroma, and advanced complicated lesions with reduced cellular components, calcification, vasa vasorum, etc.…”

“…In addition to coronary arteries and aortas, arterial lesions were observed in cerebral arteries, vertebral arteries, carotid arteries, brachiocephalic arteries, pulmonary arteries, celiac arteries, superior mesenteric arteries, renal arteries, common iliac arteries, and femoral arteries in the WHHL rabbit family fed with normal chow 13,15) . However, lesion composition depends on the arteries.…”

“…The original WHHL rabbit showed the following features: hypercholesterolemia due to LDL receptor deficiency 11,12) , low high-density lipoprotein cholesterol, atherosclerotic lesions on the aorta (Fig. 2) and various arteries except coronary lesions [13][14][15] , and other related diseases, such as xanthoma on tendons of the limb 1,16) osteonecrosis due to the abnormal accumulation of fat in osteocytes and marrow cells 17) , corneal opacities due to the infiltration of macrophages and epithelial cells 18) , sensorineural hearing loss due to inner ear cell damage 19) , and metabolic syndrome-like findings 20,21) . In addition to the characteristics of WHHL rabbits, coronary atherosclerosis occurred in WHHL-CA rabbits 2,3) , and in WHHLMI rabbits, unstable coronary lesions ( Fig.…”