{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T06:24:49Z","timestamp":1790490289457,"version":"4.1.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[1999,4,20]]},"abstract":"<jats:p>\n            <jats:italic>Background<\/jats:italic>\n            \u2014Atherosclerotic 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.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Methods and Results<\/jats:italic>\n            \u2014Lesions were quantified by computer-assisted image analysis of 30 oil red O\u2013stained 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 6.2\u00b11.3 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: 66.5\u00b110.9 \u00d710\n            <jats:sup>3<\/jats:sup>\n            \u03bcm\n            <jats:sup>2<\/jats:sup>\n            ) and the carotid (11.6\u00b15.3 \u00d710\n            <jats:sup>3<\/jats:sup>\n            \u03bcm\n            <jats:sup>2<\/jats:sup>\n            ) than in the basilar and middle cerebral artery (0.4\u00b10.1 and 0.8\u00b10.2 \u00d710\n            <jats:sup>3<\/jats:sup>\n            \u03bcm\n            <jats:sup>2<\/jats:sup>\n            , respectively;\n            <jats:italic>P<\/jats:italic>\n            &lt;0.0001). 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\u2013superoxide dismutase but not of Zn\u2013superoxide dismutase, catalase, or glutathione peroxidase were significantly higher in both intracranial arteries.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Conclusions<\/jats:italic>\n            \u2014Exposure 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\u2013mediated atherogenic processes.\n          <\/jats:p>","DOI":"10.1161\/01.cir.99.15.2003","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:42:29Z","timestamp":1339461749000},"page":"2003-2010","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":110,"title":["Intracranial Arteries of Human Fetuses Are More Resistant to Hypercholesterolemia-Induced Fatty Streak Formation Than Extracranial Arteries"],"prefix":"10.1161","volume":"99","author":[{"given":"Claudio","family":"Napoli","sequence":"first","affiliation":[{"name":"From the Department of Clinical and Experimental Medicine (C.N.), the Department of Human Pathology (F.d.N., F.P.D.), and the Department of Molecular and Cellular Biology (G.P.), Federico II University of Naples (Italy), and the Department of Medicine (C.N., J.L.W., W.P.), University of California, San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph L.","family":"Witztum","sequence":"additional","affiliation":[{"name":"From the Department of Clinical and Experimental Medicine (C.N.), the Department of Human Pathology (F.d.N., F.P.D.), and the Department of Molecular and Cellular Biology (G.P.), Federico II University of Naples (Italy), and the Department of Medicine (C.N., J.L.W., W.P.), University of California, San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena","family":"de Nigris","sequence":"additional","affiliation":[{"name":"From the Department of Clinical and Experimental Medicine (C.N.), the Department of Human Pathology (F.d.N., F.P.D.), and the Department of Molecular and Cellular Biology (G.P.), Federico II University of Naples (Italy), and the Department of Medicine (C.N., J.L.W., W.P.), University of California, San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Palumbo","sequence":"additional","affiliation":[{"name":"From the Department of Clinical and Experimental Medicine (C.N.), the Department of Human Pathology (F.d.N., F.P.D.), and the Department of Molecular and Cellular Biology (G.P.), Federico II University of Naples (Italy), and the Department of Medicine (C.N., J.L.W., W.P.), University of California, San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco P.","family":"D\u2019Armiento","sequence":"additional","affiliation":[{"name":"From the Department of Clinical and Experimental Medicine (C.N.), the Department of Human Pathology (F.d.N., F.P.D.), and the Department of Molecular and Cellular Biology (G.P.), Federico II University of Naples (Italy), and the Department of Medicine (C.N., J.L.W., W.P.), University of California, San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wulf","family":"Palinski","sequence":"additional","affiliation":[{"name":"From the Department of Clinical and Experimental Medicine (C.N.), the Department of Human Pathology (F.d.N., F.P.D.), and the Department of Molecular and Cellular Biology (G.P.), Federico II University of Naples (Italy), and the Department of Medicine (C.N., J.L.W., W.P.), University of California, San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1985.03350380096029"},{"key":"e_1_3_2_2_2","first-page":"1383","volume":"344","year":"1994","unstructured":"Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383\u20131389.","journal-title":"Lancet"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199511163332001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"60C","DOI":"10.1016\/S0002-9149(99)80472-X","volume":"76","year":"1995","unstructured":"Furberg CD, Pitt B, Byington RP, Park JS, McGovern ME. Reduction in coronary events during treatment with pravastatin: PLAC I and PLAC II Investigators: Pravastatin Limitation of Atherosclerosis in the Coronary Arteries. Am J Cardiol. 1995;76:60C\u201363C.","journal-title":"Am J Cardiol"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.92.9.2419"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199610033351401"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2796.1997.110123000.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-199508000-00008"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.27.5.929"},{"key":"e_1_3_2_10_2","first-page":"498","volume":"18","year":"1968","unstructured":"McGill HC, Arias-Stella J, Carbonell LM, Correa P, DeVeyra EA, Donoso S, Eggen DA, Galindo L, Guzman MA, Lichtenberger E, Loken C, McGarry PA, McMahan CA, Montenegro MR, Moossy J, Perez-Tamayo R, Restrepo C, Robertson WB, Salas J, Solberg LA, Strong JP, Tejada C, Wainwright J. General findings of the International Atherosclerosis Project. Lab Invest. 1968;18:498\u2013512.","journal-title":"Lab Invest"},{"key":"e_1_3_2_11_2","first-page":"351","volume":"21","year":"1977","unstructured":"Wissler RW, Vesselinovitch D. Atherosclerosis in nonhuman primates. Adv Vet Sci Comp Med. 1977;21:351\u2013420.","journal-title":"Adv Vet Sci Comp Med"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1997.03550040069040"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/str.28.5.946"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-119-2-199307150-00008"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119813"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/atv91.13.9.8364013"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115499"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.91.9.2488"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.34.20963"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2760(72)90018-5"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(90)90046-F"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.10.3.325"},{"key":"e_1_3_2_23_2","first-page":"191","volume":"125","year":"1986","unstructured":"Gown AM, Tsukada T, Ross R. Human atherosclerosis: immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986;125:191\u2013207.","journal-title":"Am J Pathol"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(76)90747-6"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(84)05016-3"},{"key":"e_1_3_2_26_2","unstructured":"Marklund SL. Pyrogallol autoxidation. In: Greenwald RA ed. CRC Handbook of Methods for Oxygen Radical Research. Boca Raton Fla: CRC Press Inc; 1985:243\u2013255."},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)52451-6"},{"key":"e_1_3_2_28_2","unstructured":"Weber G Biancardi G Cneit L Resi L Salvi M Tanganelli P. Delayed cerebral atherosclerosis involvement in WHHL rabbits. In: Crepaldi G Gotto AM Jr Manzato E Baggio G eds. Atherosclerosis VIII. Heidelberg Germany: Springer Verlag; 1989:125\u2013128."},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.85.1.1728483"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.89.5.8181179"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.4.4.341"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1042\/cs0880311"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)37560-X"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.34.1.207"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1227\/00006123-199604000-00031"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118853"},{"key":"e_1_3_2_37_2","first-page":"237","volume":"7","year":"1997","unstructured":"Palinski W, H\u00f6rkk\u00f6 S. Biological consequences of oxidation in atherosclerosis and other pathologies: lipoprotein oxidation in brain arteries. Nutr Metab Cardiovasc Dis. 1997;7:237\u2013247.","journal-title":"Nutr Metab Cardiovasc Dis"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.79.3.2917393"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/str.28.11.2266"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.19.10417"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/362801a0"},{"key":"e_1_3_2_42_2","first-page":"158","volume":"748","year":"1995","unstructured":"Libby P, Galis ZS. Cytokines regulate genes involved in atherogenesis. Ann N Y Acad Sci. 1995;748:158\u2013168.","journal-title":"Ann N Y Acad Sci"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/01.CIR.99.15.2003","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T16:40:02Z","timestamp":1715532002000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.CIR.99.15.2003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,4,20]]},"references-count":42,"journal-issue":{"issue":"15","published-print":{"date-parts":[[1999,4,20]]}},"alternative-id":["10.1161\/01.CIR.99.15.2003"],"URL":"https:\/\/doi.org\/10.1161\/01.cir.99.15.2003","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,4,20]]},"assertion":[{"value":"1998-08-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"1999-01-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1999-04-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}