Intracranial Arteries of Human Fetuses Are More Resistant to Hypercholesterolemia-Induced Fatty Streak Formation Than Extracranial Arteries

Abstract

Background-Atherosclerotic lesions in intracranial arteries occur later and are less extensive than in extracranial arteries.To investigate potential mechanisms responsible for this difference, in particular the atherogenic response to hypercholesterolemia and LDL oxidation, we compared the extent of fatty streak formation and the composition of these very early lesions in intracranial arteries of human fetuses from normocholesterolemic and hypercholesterolemic mothers with those in extracranial arteries. Methods and Results-Lesions were quantified by computer-assisted image analysis of 30 oil red O-stained sections, each from the middle cerebral, basilar, and common carotid arteries and the abdominal aorta of human fetuses (spontaneous abortions and premature newborns who died within 12 hours of birth; both of fetal age 6.2Ϯ1.3 months) from 43 hypercholesterolemic mothers and 34 normocholesterolemic mothers. Macrophages, apolipoprotein B, and 2 epitopes of oxidized LDL in lesions were determined immunocytochemically. Activities of superoxide dismutase, catalase, and glutathione peroxidase in the arterial wall were also determined. Lesion numbers and sizes were dramatically greater in the abdominal aorta (area of the largest lesion per section: 66.5Ϯ10.9 ϫ10 3 m 2 ) and the carotid (11.6Ϯ5.3 ϫ10 3 m 2 ) than in the basilar and middle cerebral artery (0.4Ϯ0.1 and 0.8Ϯ0.2 ϫ10 3 m 2 , respectively; PϽ0.0001). Hypercholesterolemia resulted in a significant increase of lesion size in extracranial arteries but only a marginal increase in intracranial arteries. In analogy, hypercholesterolemia induced a much greater increase in the intimal presence of macrophages, apolipoprotein B, and oxidized LDL (oxidation-specific epitopes) in extracranial than in intracranial arteries. Immunocytochemistry did not indicate that lesions of intracranial arteries contain relatively less oxidized LDL than similar-size lesions of extracranial arteries. Activities of Mn-superoxide dismutase but not of Zn-superoxide dismutase, catalase, or glutathione peroxidase were significantly higher in both intracranial arteries. Conclusions-Exposure to hypercholesterolemia during fetal development results in extensive formation of fatty streaks in extracranial but not intracranial arteries. The fact that such a difference in lesion formation occurs in the absence of many other atherogenic risk factors found later in life suggests that differences in the atherogenic response to hypercholesterolemia are an important contributor to the slower onset of the disease in intracranial vessels in adults. Fetal arteries may allow elucidation of the mechanisms responsible, for example, better protection of intracranial arteries against free radical-mediated atherogenic processes. (Circulation.

Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice

“…Mice were killed with a lethal dose of sodium pentobarbital 21 days after injury and a 24-gauge needle was placed in the left portion of the aortic arch (ascendent aorta) to achieve in situ perfusion fixation of the carotid arteries at physiologic pressure (100 mm Hg) with phosphate-buffered paraformaldehyde (4%, 0.1 M, pH 7.3) for histology and normal saline for immunohistochemistry assessed by computer-assisted imaging analysis (25,27,28). At this time, histologic analysis of the gastrointestinal system indicated both a severe mucosal and ulcerogenic damage induced by aspirin, but not by NCX-4016 (data not shown).…”

“…Carotid arteries were serially sectioned in 15-20 slices (10 M) with a rotating diamond-coated knife (Leica, Deerfield, IL), and sections were stained with toluidine blue. The length of the external elastic lamina, the area confined by the internal elastic lamina, and the cross-sectional neointimal area were measured by morphometry (27,28). The vessel injury score was determined according to the original method devised by Schwartz et al (29), adapted for mice (22,26).…”

“…In additional sections, atherosclerotic carotid artery lesions were determined by oil-red O stained sections using computer-assisted imaging (25,27,28). Total cell number and number of proliferating cells in the neointima of the arterial cross sections were determined by computer-assisted imaging cell counting after immunohistochemistry of serial sections with ␣-actin monoclonal mouse antibody (M0858 from Dako), and antibody against proliferating cell nuclear antigen (PCNA, 1:250 dilution; clone PC10 from Dako; the adjacent medial layer of vessels served as positive control) (27,28). Macrophage-derived foam cells were stained by the F4͞80 antibody (1:500 dilution; Accurate Scientific, Westbury, NY) (27,28).…”

“…Additional experiments were also performed with F4͞80/PCNA double staining. Epitopes recognized by the primary antibody were detected by an avidin-biotin-peroxidase method (27,28).…”

Taurine Attenuates Hepatic and Cardiac Damage and Apoptosis in Rabbits Fed a High-Fat Diet

“…Hypercholesterolemia results in free radical production and thereby elevates lipid peroxides. Experimental hypercholesterolemia is associated with an increased production of reactive oxygen species and decreased activities of endogenous radical scavengers (Napol et al, 1999). Elevated blood concentration of cholesterol, especially in LDL, constitutes the primary risk factor for atherosclerosis and endothelial dysfunction (Bonetti et al, 2003).…”