title: Endothelial dysfunction in the apolipoprotein E-deficient mouse: insights into the influence of diet, gender and aging.
abstract: Since the early 1990s, several strains of genetically modified mice have been developed as models for experimental atherosclerosis. Among the available models, the apolipoprotein E-deficient (apoE⁻/⁻) mouse is of particular relevance because of its propensity to spontaneously develop hypercholesterolemia and atherosclerotic lesions that are similar to those found in humans, even when the mice are fed a chow diet. The main purpose of this review is to highlight the key achievements that have contributed to elucidating the mechanisms pertaining to vascular dysfunction in the apoE⁻/⁻ mouse. First, we summarize lipoproteins and atherosclerosis phenotypes in the apoE⁻/⁻ mouse, and then we briefly discuss controversial evidence relative to the influence of gender on the development of atherosclerosis in this murine model. Second, we discuss the main mechanisms underlying the endothelial dysfunction of conducting vessels and resistance vessels and examine how this vascular defect can be influenced by diet, aging and gender in the apoE⁻/⁻ mouse.
authors.affiliation: Departament of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
authors.forename: Silvana S
authors.initials: SS
authors.lastname: Meyrelles
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Peotta
authors.forename: Thiago M C
authors.initials: TM
authors.lastname: Pereira
authors.forename: Elisardo C
authors.initials: EC
authors.lastname: Vasquez
mesh_terms: D000375:Aging; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy; D004032:Diet; D004195:Disease Models, Animal; D004727:Endothelium / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D012727:Sex Characteristics
chemical_list: D001057:Apolipoproteins E; D008074:Lipoproteins
references.citation: Circ Res. 1983 Jul;53(1):63-71
references.pmid: 6861297
references.citation: Curr Drug Targets. 2007 Nov;8(11):1172-80
references.pmid: 18045095
references.citation: Circulation. 2004 Jun 1;109(21 Suppl 1):II27-33
references.pmid: 15173060
references.citation: Atherosclerosis. 2011 Dec;219(2):545-51
references.pmid: 21944698
references.citation: Life Sci. 2004 Jul 23;75(10):1255-61
references.pmid: 15219813
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14367-72
references.pmid: 9826706
references.citation: Exp Biol Med (Maywood). 2006 Jun;231(6):806-12
references.pmid: 16741003
references.citation: Basic Res Cardiol. 1994;89 Suppl 1:87-102
references.pmid: 7945179
references.citation: Circulation. 2004 Dec 21;110(25):3849-57
references.pmid: 15596561
references.citation: Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1606-13
references.pmid: 20448208
references.citation: Lipids Health Dis. 2011 May 17;10:80
references.pmid: 21586133
references.citation: Hypertens Res. 2011 Jan;34(1):5-14
references.pmid: 20981034
references.citation: J Clin Invest. 2001 Nov;108(10):1513-22
references.pmid: 11714743
references.citation: Reprod Sci. 2010 Jun;17(6):511-31
references.pmid: 20460551
references.citation: Clin Sci (Lond). 2002 Mar;102(3):321-7
references.pmid: 11869173
references.citation: Mol Carcinog. 2007 Dec;46(12):993-1002
references.pmid: 17538954
references.citation: Atherosclerosis. 1987 Dec;68(3):231-40
references.pmid: 3426656
references.citation: Basic Res Cardiol. 2010 Jul;105(4):479-86
references.pmid: 20177692
references.citation: Circulation. 2001 Mar 6;103(9):1282-8
references.pmid: 11238274
references.citation: Cell. 1992 Oct 16;71(2):343-53
references.pmid: 1423598
references.citation: Antioxid Redox Signal. 2011 Sep 15;15(6):1583-606
references.pmid: 21473702
references.citation: Proc Natl Acad Sci U S A. 1992 May 15;89(10):4471-5
references.pmid: 1584779
references.citation: Br J Pharmacol. 2011 Apr;162(7):1564-76
references.pmid: 21175571
references.citation: J Vasc Res. 2003 Mar-Apr;40(2):87-96
references.pmid: 12808344
references.citation: J Clin Endocrinol Metab. 1995 Nov;80(11):3191-5
references.pmid: 7593425
references.citation: Am J Physiol. 1999 Apr;276(4):R1023-9
references.pmid: 10198381
references.citation: Am J Physiol Heart Circ Physiol. 2000 Feb;278(2):H428-34
references.pmid: 10666072
references.citation: Exp Biol Med (Maywood). 2006 Mar;231(3):237-51
references.pmid: 16514169
references.citation: J Physiol Pharmacol. 2010 Jun;61(3):309-16
references.pmid: 20610861
references.citation: Circulation. 1991 Nov;84(5):1984-92
references.pmid: 1934373
references.citation: Atherosclerosis. 2007 Jan;190(1):35-42
references.pmid: 16529753
references.citation: Clin Sci (Lond). 2009 Jul 16;117(4):139-55
references.pmid: 19601928
references.citation: Hypertension. 2009 Nov;54(5):1043-9
references.pmid: 19770400
references.citation: Circ J. 2002 Nov;66(11):1057-9
references.pmid: 12419940
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Dec;283(6):R1442-9
references.pmid: 12388474
references.citation: Stroke. 2007 Jul;38(7):2136-41
references.pmid: 17525390
references.citation: Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2333-40
references.pmid: 9409199
references.citation: Br J Pharmacol. 1993 Sep;110(1):151-8
references.pmid: 7693274
references.citation: Arterioscler Thromb Vasc Biol. 1999 Nov;19(11):2762-8
references.pmid: 10559023
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9747-52
references.pmid: 10944233
references.citation: Am J Physiol. 1999 Apr;276(4):H1346-54
references.pmid: 10199861
references.citation: Science. 1988 Apr 29;240(4852):622-30
references.pmid: 3283935
references.citation: Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):809-14
references.pmid: 15692095
references.citation: Circulation. 2004 Nov 9;110(19):3062-7
references.pmid: 15277329
references.citation: Free Radic Biol Med. 2000 Oct 15;29(8):704-13
references.pmid: 11053771
references.citation: Circ Res. 2001 Oct 26;89(9):793-8
references.pmid: 11679409
references.citation: Circulation. 2002 Aug 20;106(8):927-32
references.pmid: 12186795
references.citation: Clin Sci (Lond). 2005 Sep;109(3):217-26
references.pmid: 16104842
references.citation: PLoS One. 2009 Oct 13;4(10):e7430
references.pmid: 19823587
references.citation: J Atheroscler Thromb. 2010 May;17(5):431-5
references.pmid: 20215708
references.citation: Basic Res Cardiol. 2005 Mar;100(2):102-11
references.pmid: 15578196
references.citation: J Lipid Res. 1995 Nov;36(11):2320-8
references.pmid: 8656070
references.citation: Circulation. 2001 Jul 24;104(4):448-54
references.pmid: 11468208
references.citation: Braz J Med Biol Res. 2009 Dec;42(12):1191-5
references.pmid: 19893993
references.citation: Cardiovasc Res. 2008 Apr 1;78(1):123-9
references.pmid: 18079107
references.citation: Cardiovasc Res. 2002 Feb 1;53(2):487-95
references.pmid: 11827700
references.citation: Eur J Pharmacol. 2001 Jul 20;424(2):141-9
references.pmid: 11476760
references.citation: Basic Res Cardiol. 2011 Sep;106(5):735-47
references.pmid: 21598086
references.citation: Stroke. 2001 Nov;32(11):2658-64
references.pmid: 11692031
references.citation: Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):183-9
references.pmid: 12588757
references.citation: J Clin Invest. 2000 Dec;106(12):1521-30
references.pmid: 11120759
references.citation: Cardiovasc Res. 2002 Jan;53(1):253-62
references.pmid: 11744035
references.citation: Circulation. 2003 May 20;107(19):2480-6
references.pmid: 12719275
references.citation: Circulation. 2008 May 6;117(18):2377-87
references.pmid: 18443241
references.citation: Int J Mol Med. 2002 Jun;9(6):659-64
references.pmid: 12011985
references.citation: Atherosclerosis. 2007 Nov;195(1):75-82
references.pmid: 17275002
references.citation: Curr Hypertens Rep. 2000 Apr;2(2):167-73
references.pmid: 10981145
references.citation: Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2679-84
references.pmid: 9409242
references.citation: J Clin Invest. 1997 Jan 1;99(1):41-6
references.pmid: 9011574
references.citation: Lipids Health Dis. 2011 Sep 06;10:155
references.pmid: 21896159
references.citation: Circulation. 2001 Jan 23;103(3):448-54
references.pmid: 11157699
references.citation: Arterioscler Thromb. 1994 Jan;14(1):133-40
references.pmid: 8274468
references.citation: Br J Pharmacol. 2008 Feb;153(3):508-16
references.pmid: 18059326
references.citation: J Atheroscler Thromb. 2010 Jul 30;17(7):712-21
references.pmid: 20460831
references.citation: J Am Coll Cardiol. 2004 Sep 15;44(6):1311-9
references.pmid: 15364338
references.citation: Trends Pharmacol Sci. 2002 Aug;23(8):374-80
references.pmid: 12377579
references.citation: Circ Res. 2000 Nov 10;87(10):840-4
references.pmid: 11073878
references.citation: Circulation. 1999 Sep 14;100(11):1230-5
references.pmid: 10484545
references.citation: J Clin Invest. 1994 Sep;94(3):937-45
references.pmid: 8083379
references.citation: Free Radic Biol Med. 2006 Oct 15;41(8):1289-303
references.pmid: 17015176
references.citation: J Cardiovasc Pharmacol. 2000 Dec;36(6):751-7
references.pmid: 11117375
references.citation: Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):871-7
references.pmid: 17272755
references.citation: Am J Physiol Heart Circ Physiol. 2001 Sep;281(3):H981-6
references.pmid: 11514262
references.citation: J Am Coll Cardiol. 1999 Sep;34(3):631-8
references.pmid: 10483941
references.citation: J Vasc Surg. 2011 Mar;53(3):754-63
references.pmid: 21163611
references.citation: Circulation. 1997 Mar 18;95(6):1542-8
references.pmid: 9118523
references.citation: Hypertension. 2000 Oct;36(4):638-41
references.pmid: 11040250
references.citation: Br J Pharmacol. 2003 Jul;139(6):1127-34
references.pmid: 12871831
references.citation: Pharmacol Res. 2004 Jun;49(6):543-9
references.pmid: 15026032
references.citation: Acta Histochem. 2006;108(6):415-24
references.pmid: 17007910
references.citation: Am J Physiol Heart Circ Physiol. 2003 Dec;285(6):H2255-63
references.pmid: 14613908
references.citation: Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):653-61
references.pmid: 19910640
references.citation: Arterioscler Thromb Vasc Biol. 2001 Jun;21(6):1017-22
references.pmid: 11397713
references.citation: Am J Physiol Heart Circ Physiol. 2008 Dec;295(6):H2503-11
references.pmid: 18952716
references.citation: Cardiovasc Res. 2005 Oct 1;68(1):26-36
references.pmid: 16009356
references.citation: Clin Sci (Lond). 2005 Jun;108(6):531-8
references.pmid: 15675896
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1110-9
references.pmid: 17626122
references.citation: Am J Pathol. 1993 Oct;143(4):987-1002
references.pmid: 8214014
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10022-7
references.pmid: 8816744
references.citation: J Physiol Pharmacol. 2004 Sep;55(3):503-17
references.pmid: 15381823
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8314-8
references.pmid: 8378301
references.citation: Pharmacol Rep. 2009 Jan-Feb;61(1):105-15
references.pmid: 19307698
references.citation: Circ Res. 1984 Jun;54(6):711-8
references.pmid: 6733866
references.citation: Cardiovasc Res. 2008 Jan;77(1):178-87
references.pmid: 18006471
references.citation: Lipids Health Dis. 2010 May 19;9:51
references.pmid: 20482882
references.citation: Lipids Health Dis. 2010 Aug 19;9:87
references.pmid: 20723257
references.citation: Arterioscler Thromb Vasc Biol. 2006 Oct;26(10):2331-6
references.pmid: 16873728
references.citation: Science. 1992 Oct 16;258(5081):468-71
references.pmid: 1411543
references.citation: Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1006-14
references.pmid: 15087308
references.citation: Hypertension. 2005 Oct;46(4):932-6
references.pmid: 16087779
references.citation: Circulation. 1999 Apr 20;99(15):2027-33
references.pmid: 10209008
references.citation: Atherosclerosis. 1987 Apr;64(2-3):215-21
references.pmid: 3606719
references.citation: Atherosclerosis. 1999 Aug;145(2):301-8
references.pmid: 10488957
references.citation: Circ Res. 2006 Oct 13;99(8):e74-83
references.pmid: 16990568
references.citation: Pflugers Arch. 2008 Feb;455(5):811-8
references.pmid: 17899169
references.citation: J Vasc Res. 2005 Nov-Dec;42(6):475-82
references.pmid: 16155363
references.citation: Circulation. 2002 Apr 2;105(13):1541-4
references.pmid: 11927518
references.citation: Am J Cardiol. 1991 Dec 1;68(15):1425-30
references.pmid: 1746422
references.citation: Cardiovasc Res. 2003 Jul 1;59(1):189-99
references.pmid: 12829190
references.citation: Arterioscler Thromb Vasc Biol. 2000 Apr;20(4):1033-9
references.pmid: 10764669
references.citation: Hypertension. 2004 Sep;44(3):277-82
references.pmid: 15302839
references.citation: Nat Clin Pract Cardiovasc Med. 2006 Feb;3(2):94-101
references.pmid: 16446778
references.citation: Circulation. 2004 Jun 15;109(23 Suppl 1):III27-32
references.pmid: 15198963
references.citation: Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H985-1002
references.pmid: 16632549
references.citation: Circ Res. 2007 Jan 5;100(1):15-26
references.pmid: 17204661