title: Cellular and molecular biology of aging endothelial cells.
abstract: Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction results from a reduction in nitric oxide bioavailability downstream of endothelial oxidative stress and inflammation that can be further modulated by traditional CVD risk factors in older adults. Greater endothelial oxidative stress with aging is a result of augmented production from the intracellular enzymes NADPH oxidase and uncoupled eNOS, as well as from mitochondrial respiration in the absence of appropriate increases in antioxidant defenses as regulated by relevant transcription factors, such as FOXO. Interestingly, it appears that NFkB, a critical inflammatory transcription factor, is sensitive to this age-related endothelial redox change and its activation induces transcription of pro-inflammatory cytokines that can further suppress endothelial function, thus creating a vicious feed-forward cycle. This review will discuss the two macro-mechanistic processes, oxidative stress and inflammation, that contribute to endothelial dysfunction with advancing age as well as the cellular and molecular events that lead to the vicious cycle of inflammation and oxidative stress in the aged endothelium. Other potential mediators of this pro-inflammatory endothelial phenotype are increases in immune or senescent cells in the vasculature. Of note, genomic instability, telomere dysfunction or DNA damage has been shown to trigger cell senescence via the p53/p21 pathway and result in increased inflammatory signaling in arteries from older adults. This review will discuss the current state of knowledge regarding the emerging concepts of senescence and genomic instability as mechanisms underlying oxidative stress and inflammation in the aged endothelium. Lastly, energy sensitive/stress resistance pathways (SIRT-1, AMPK, mTOR) are altered in endothelial cells and/or arteries with aging and these pathways may modulate endothelial function via key oxidative stress and inflammation-related transcription factors. This review will also discuss what is known about the role of "energy sensing" longevity pathways in modulating endothelial function with advancing age. With the growing population of older adults, elucidating the cellular and molecular mechanisms of endothelial dysfunction with age is critical to establishing appropriate and measured strategies to utilize pharmacological and lifestyle interventions aimed at alleviating CVD risk. This article is part of a Special Issue entitled "SI: CV Aging".
authors: University of Utah, Department of Internal Medicine, Division of Geriatrics, Salt Lake City, UT, USA; Veteran's Affairs Medical Center-Salt Lake City, Geriatrics Research Education and Clinical Center, Salt Lake City, UT, USA. Electronic address: tony.donato@utah.edu.
authors: Anthony J
authors: AJ
authors: Donato
authors: University of Washington, Department of Pathology, Seattle, WA, USA.
authors: R Garrett
authors: RG
authors: Morgan
authors: University of Utah, Department of Internal Medicine, Division of Geriatrics, Salt Lake City, UT, USA.
authors: Ashley E
authors: AE
authors: Walker
authors: University of Utah, Department of Internal Medicine, Division of Geriatrics, Salt Lake City, UT, USA; Veteran's Affairs Medical Center-Salt Lake City, Geriatrics Research Education and Clinical Center, Salt Lake City, UT, USA.
authors: Lisa A
authors: LA
authors: Lesniewski
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000473:pathology; D016922:Cellular Senescence; D042783:Endothelial Cells / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology; D004734:Energy Metabolism; D042822:Genomic Instability; D006801:Humans
keywords: Aging; Endothelium; Genomic instability; Inflammation; Oxidative stress; Senescence
references: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1649-54
references: 15668399
references: Biochem Biophys Res Commun. 1997 Aug 18;237(2):340-4
references: 9268712
references: Free Radic Biol Med. 2008 Nov 1;45(9):1340-51
references: 18760347
references: Am J Physiol Cell Physiol. 2006 Feb;290(2):C433-43
references: 16162660
references: Br J Pharmacol. 1990 Jul;100(3):463-6
references: 2390671
references: Circulation. 1999 Jul 27;100(4):354-60
references: 10421594
references: Free Radic Res Commun. 1992;17(4):221-37
references: 1473734
references: Mol Cell. 2005 Apr 29;18(3):283-93
references: 15866171
references: Curr Biol. 2004 May 25;14(10):885-90
references: 15186745
references: Am J Physiol Heart Circ Physiol. 2012 Sep 15;303(6):H672-9
references: 22821989
references: BMC Syst Biol. 2009;3:31
references: 19284563
references: FASEB J. 2002 Sep;16(11):1423-5
references: 12205035
references: Hypertension. 1996 Sep;28(3):488-93
references: 8794838
references: Circ Res. 2009 Feb 27;104(4):496-505
references: 19131647
references: Annu Rev Pathol. 2010;5:99-118
references: 20078217
references: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14855-60
references: 17785417
references: Cell. 1997 Mar 7;88(5):593-602
references: 9054499
references: Biochem J. 2000 Jun 15;348 Pt 3:607-14
references: 10839993
references: Annu Rev Immunol. 2000;18:621-63
references: 10837071
references: Nature. 1990 May 31;345(6274):458-60
references: 2342578
references: Aging Cell. 2010 Jun;9(3):304-12
references: 20121721
references: J Physiol. 2004 Apr 1;556(Pt 1):315-24
references: 14754992
references: Hypertension. 1999 Jan;33(1):116-23
references: 9931091
references: Am J Physiol Lung Cell Mol Physiol. 2001 Jun;280(6):L1094-103
references: 11350788
references: Cell. 2005 Feb 25;120(4):513-22
references: 15734683
references: FASEB J. 2003 Nov;17(14):1975-85
references: 14597667
references: Development. 2004 Aug;131(16):3897-906
references: 15253933
references: Antioxid Redox Signal. 2000 Winter;2(4):919-35
references: 11213492
references: Hypertension. 1998 Feb;31(2):643-8
references: 9461235
references: Circ Res. 2010 Apr 30;106(8):1384-93
references: 20203304
references: Cell. 2003 Jun 13;113(6):703-16
references: 12809602
references: Circulation. 2002 Apr 2;105(13):1541-4
references: 11927518
references: Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H2634-43
references: 17873024
references: Cardiovasc Res. 2000 Aug 18;47(3):549-55
references: 10963727
references: Eur J Pharmacol. 2011 Jan 25;651(1-3):41-50
references: 21114978
references: J Physiol. 2003 Jan 1;546(Pt 1):289-98
references: 12509496
references: Science. 2004 Mar 26;303(5666):2011-5
references: 14976264
references: J Biol Chem. 2001 Jun 22;276(25):22586-94
references: 11316812
references: Nature. 2011 Nov 10;479(7372):232-6
references: 22048312
references: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2497-506
references: 18375721
references: Arterioscler Thromb Vasc Biol. 2011 Apr;31(4):876-82
references: 21273559
references: Am J Physiol Heart Circ Physiol. 2009 Sep;297(3):H1087-95
references: 19617414
references: Fertil Steril. 2003 Dec;80(6):1420-30
references: 14667878
references: J Am Coll Cardiol. 2003 Oct 1;42(7):1149-60
references: 14522472
references: Biochem Biophys Res Commun. 1996 Aug 5;225(1):186-90
references: 8769115
references: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4193-8
references: 9108128
references: Aging Dis. 2014 Apr 01;5(2):114-25
references: 24729937
references: Age (Dordr). 2014 Apr;36(2):559-69
references: 24065292
references: Can J Physiol Pharmacol. 2004 Mar;82(3):200-7
references: 15052286
references: Aging Cell. 2012 Aug;11(4):675-82
references: 22587563
references: Hypertension. 2014 Feb;63(2):390-6
references: 24296279
references: Genes Dev. 1994 Nov 1;8(21):2540-51
references: 7958916
references: J Biol Chem. 2007 Mar 30;282(13):9777-88
references: 17255104
references: Am J Physiol Heart Circ Physiol. 2006 Oct;291(4):H1694-9
references: 16973825
references: Clin Cardiol. 1997 Nov;20(11 Suppl 2):II-11-7
references: 9422847
references: PLoS Biol. 2008 Dec 2;6(12):2853-68
references: 19053174
references: Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):413-20
references: 14656731
references: Am J Hum Genet. 2006 Sep;79(3):469-80
references: 16909385
references: Physiol Genomics. 2008 Feb 19;32(3):409-18
references: 18056786
references: Nat Cell Biol. 2003 Aug;5(8):741-7
references: 12855956
references: J Appl Physiol (1985). 2008 Oct;105(4):1359-63
references: 18669935
references: Curr Biol. 2004 Dec 29;14(24):2302-8
references: 15620660
references: Nat Cell Biol. 2009 Nov;11(11):1325-31
references: 19855388
references: Mol Cell. 2008 Jun 20;30(6):701-11
references: 18570873
references: J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94
references: 19812304
references: Cardiovasc Res. 2012 Jan 1;93(1):111-9
references: 22002459
references: EMBO J. 2002 Jun 17;21(12):2936-45
references: 12065407
references: J Clin Endocrinol Metab. 2003 May;88(5):2087-95
references: 12727959
references: Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1493-9
references: 10845863
references: Circulation. 1998 Oct 13;98(15):1504-9
references: 9769303
references: Biochem Soc Trans. 2006 Nov;34(Pt 5):731-4
references: 17052184
references: J Biol Chem. 2003 Aug 15;278(33):31000-6
references: 12788940
references: Cell Metab. 2008 Aug;8(2):157-68
references: 18599363
references: J Biol Chem. 2006 Mar 3;281(9):5657-67
references: 16407283
references: Hypertension. 2010 Feb;55(2):363-9
references: 20048194
references: Aging Cell. 2008 Dec;7(6):805-12
references: 18782346
references: Arq Bras Cardiol. 2005 Jul;85(1):15-9
references: 16041449
references: J Exp Med. 1994 Feb 1;179(2):503-12
references: 7507507
references: Nature. 2000 Feb 17;403(6771):795-800
references: 10693811
references: Hypertension. 2001 Aug;38(2):274-9
references: 11509489
references: J Biol Chem. 2010 Jun 18;285(25):19051-9
references: 20421294
references: Exp Gerontol. 2004 Sep;39(9):1369-78
references: 15489060
references: Curr Protein Pept Sci. 2008 Oct;9(5):478-92
references: 18855699
references: Circulation. 2000 Jun 27;101(25):2896-901
references: 10869260
references: Mech Ageing Dev. 2012 May;133(5):368-71
references: 22484146
references: J Biol Chem. 2010 May 14;285(20):15346-55
references: 20233722
references: Clin Cardiol. 1997 Nov;20(11 Suppl 2):II-3-10
references: 9422846
references: Biochem Biophys Res Commun. 1996 Mar 7;220(1):137-40
references: 8602833
references: Am J Pathol. 2007 Jan;170(1):388-98
references: 17200210
references: Cell. 2001 Oct 19;107(2):137-48
references: 11672522
references: Arch Physiol Biochem. 2007 Oct-Dec;113(4-5):163-72
references: 18158642
references: Circulation. 2013 Jan 22;127(3):386-96
references: 23224247
references: Biochemistry. 1998 Feb 10;37(6):1613-22
references: 9484232
references: J Physiol. 2009 Aug 1;587(Pt 15):3885-97
references: 19528246
references: Am J Respir Crit Care Med. 2010 Nov 1;182(9):1153-60
references: 20581168
references: Science. 1990 Sep 28;249(4976):1570-4
references: 2218499
references: J Leukoc Biol. 2004 Jun;75(6):1156-65
references: 14982945
references: J Steroid Biochem Mol Biol. 2009 Nov;117(4-5):99-106
references: 19635557
references: Diabetologia. 2011 Dec;54(12):3101-10
references: 21947382
references: Circulation. 2011 Apr 19;123(15):1650-60
references: 21502583
references: Mol Cell Biol Res Commun. 2000 Jul;4(1):62-5
references: 11152629
references: Cell Signal. 2012 Apr;24(4):835-45
references: 22182507
references: Int J Mol Med. 2005 Aug;16(2):237-43
references: 16012755
references: J Biol Chem. 2011 Oct 21;286(42):36396-403
references: 21880712
references: Cell Rep. 2014 Mar 13;6(5):836-43
references: 24582957
references: Circ Res. 2011 Aug 19;109(5):543-53
references: 21719760
references: Mol Interv. 2006 Feb;6(1):36-47
references: 16507749
references: Nature. 2003 Dec 11;426(6967):620
references: 14668850
references: Circulation. 1995 Apr 1;91(7):1981-7
references: 7895356
references: J Physiol. 2006 Jul 1;574(Pt 1):7-15
references: 16644800
references: Mech Ageing Dev. 2003 Aug-Sep;124(8-9):911-9
references: 14499496
references: Circ Res. 2000 Mar 17;86(5):494-501
references: 10720409
references: Circulation. 2009 Mar 10;119(9):1284-92
references: 19237660
references: Nature. 2001 Mar 8;410(6825):227-30
references: 11242085
references: Circ Res. 2006 Jul 21;99(2):156-64
references: 16794190
references: Ann Med. 2007;39(5):335-45
references: 17701476
references: J Cardiovasc Pharmacol. 2000 Aug;36(2):182-7
references: 10942159
references: Free Radic Biol Med. 1998 Apr;24(6):885-93
references: 9607597
references: Circulation. 2000 Sep 19;102(12):1351-7
references: 10993851
references: J Gerontol A Biol Sci Med Sci. 2007 Mar;62(3):235-45
references: 17389720
references: Nat Genet. 1994 Sep;8(1):66-9
references: 7987394
references: Exp Gerontol. 2004 May;39(5):687-99
references: 15130663
references: Curr Opin Cell Biol. 2001 Jun;13(3):332-7
references: 11343904
references: Am J Physiol Heart Circ Physiol. 2010 Feb;298(2):H671-8
references: 19966056
references: Exp Cell Res. 1965 Mar;37:614-36
references: 14315085
references: Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H425-32
references: 19465546
references: Circ Res. 2007 Jun 8;100(11):1659-66
references: 17478731
references: Hypertension. 1996 Apr;27(4):849-53
references: 8613259
references: FEBS Lett. 1999 Jan 29;443(3):285-9
references: 10025949
references: Circ Res. 2009 Jul 17;105(2):114-27
references: 19608989
references: Circ Res. 2000 May 12;86(9):960-6
references: 10807868
references: Nucleic Acids Res. 2007;35(20):6984-94
references: 17940099
references: J Physiol Pharmacol. 2011 Oct;62(5):583-7
references: 22204807
references: Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2121-8
references: 18326800
references: Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):1941-6
references: 17556650
references: Ann N Y Acad Sci. 1998 Nov 20;854:102-17
references: 9928424
references: J Clin Invest. 2012 Jul;122(7):2601-12
references: 22706308
references: J Physiol. 2005 Nov 1;568(Pt 3):1057-65
references: 16141271
references: J Appl Physiol (1985). 2002 Nov;93(5):1685-90
references: 12381754
references: Circulation. 2003 Oct 28;108(17):2049-53
references: 14581383
references: J Physiol. 2004 May 1;556(Pt 3):947-58
references: 15004211
references: Cell. 2001 Oct 19;107(2):149-59
references: 11672523
references: Circ Res. 2000 Nov 10;87(10):840-4
references: 11073878
references: Hypertension. 2001 Feb;37(2 Pt 2):529-34
references: 11230330
references: Circ Res. 2005 Apr 29;96(8):838-46
references: 15790954
references: Am J Clin Nutr. 2007 Aug;86(2):334-40
references: 17684202
references: Med Clin North Am. 2009 May;93(3):583-604, Table of Contents
references: 19427493
references: Exp Biol Med (Maywood). 2008 Jan;233(1):21-31
references: 18156302
references: Cell Metab. 2005 May;1(5):287-8
references: 16054073
references: Nat Cell Biol. 2008 Apr;10(4):452-9
references: 18311132
references: Biol Chem. 2008 Mar;389(3):279-83
references: 18208360
references: Eur J Pharmacol. 2011 Oct 15;668(3):373-82
references: 21806981
references: Nature. 2003 Nov 13;426(6963):194-8
references: 14608368
references: Hypertension. 2004 Aug;44(2):134-9
references: 15249547
references: Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H3119-27
references: 17337602
references: EMBO J. 2004 Jun 16;23(12):2369-80
references: 15152190
references: Semin Immunol. 2000 Feb;12(1):85-98
references: 10723801
references: Circulation. 2012 Mar 6;125(9):1122-33
references: 22302838
references: Nature. 2006 Dec 14;444(7121):868-74
references: 17167475
references: Br J Nutr. 2001 Aug;86 Suppl 1:S121-7
references: 11520430
references: Mech Ageing Dev. 2009 Aug;130(8):518-27
references: 19549533
references: Biochem Biophys Res Commun. 2008 Oct 24;375(3):414-9
references: 18721796
references: Eur J Pharmacol. 2012 Nov 15;695(1-3):88-95
references: 22921370
references: Circulation. 2010 May 25;121(20):2200-10
references: 20458013
references: J Gerontol A Biol Sci Med Sci. 2009 Jan;64(1):9-20
references: 19211548
references: Hypertension. 2007 Jul;50(1):219-27
references: 17452499
references: Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40
references: 17667954
references: Atherosclerosis. 2012 Dec;225(2):296-303
references: 23078884
references: Genes Dev. 2006 Jan 15;20(2):174-84
references: 16418483
references: J Appl Physiol (1985). 2005 Nov;99(5):1872-9
references: 16024519
references: Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):646-55
references: 10073969
references: J Appl Physiol (1985). 2013 Mar 1;114(5):681-93
references: 23288555
references: Biochem Pharmacol. 2003 Aug 1;66(3):439-45
references: 12907243
references: Nature. 2009 Jul 16;460(7253):392-5
references: 19587680
references: Hypertension. 2000 Jun;35(6):1237-41
references: 10856270
references: Am J Physiol Cell Physiol. 2003 Aug;285(2):C343-52
references: 12700137
references: Annu Rev Pathol. 2009;4:71-95
references: 18754744
references: J Biol Chem. 1994 Dec 2;269(48):30077-80
references: 7982907
references: Cell Physiol Biochem. 2013;32(5):1167-77
references: 24335167
references: Am J Hypertens. 2009 Mar;22(3):250-6
references: 19114985
references: Exp Gerontol. 2014 Apr;52:9-17
references: 24463049
references: EMBO J. 1991 Aug;10(8):2247-58
references: 2065663
references: J Physiol. 2006 Mar 15;571(Pt 3):661-8
references: 16439428
references: Atherosclerosis. 2000 Dec;153(2):397-402
references: 11164429
references: J Biol Chem. 2007 Oct 12;282(41):30107-19
references: 17711846
references: J Biol Chem. 2007 Jul 13;282(28):20351-64
references: 17519230
references: J Mol Med (Berl). 2011 Jul;89(7):667-76
references: 21431325
references: Circ Res. 1998 Aug 10;83(3):279-86
references: 9710120
references: Curr Biol. 2003 Sep 2;13(17):1549-56
references: 12956959
references: J Gerontol A Biol Sci Med Sci. 2011 Aug;66(8):866-75
references: 21622983
references: EMBO J. 2002 May 1;21(9):2180-8
references: 11980715
references: Pharmacol Rev. 1991 Jun;43(2):109-42
references: 1852778
references: N Engl J Med. 1993 Dec 30;329(27):2002-12
references: 7504210
references: Cancer Cell. 2007 Jul;12(1):9-22
references: 17613433
references: Science. 2009 Oct 2;326(5949):140-4
references: 19797661
references: PLoS One. 2013;8(1):e54514
references: 23342163
references: Am J Physiol Heart Circ Physiol. 2014 Dec 15;307(12):H1754-63
references: 25326534
references: Am J Physiol. 1995 Jun;268(6 Pt 2):H2288-93
references: 7611479
references: Hypertension. 2009 Jun;53(6):973-8
references: 19414649
references: Am J Hypertens. 2005 Apr;18(4 Pt 1):510-6
references: 15831361
references: J Physiol. 2011 Sep 15;589(Pt 18):4545-54
references: 21746786
references: Circ Res. 2003 Feb 7;92(2):e31-40
references: 12574154
references: J Am Coll Cardiol. 1994 Aug;24(2):471-6
references: 8034885
references: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8204-9
references: 15928081
references: Genes Dev. 2011 Oct 15;25(20):2125-36
references: 21979375
references: Clin Sci (Lond). 2011 May;120(9):357-75
references: 21244363
references: Circulation. 1993 Oct;88(4 Pt 1):1456-62
references: 8403292
references: Nature. 2012 Dec 13;492(7428):252-5
references: 23143332
references: Mech Ageing Dev. 2007 Sep;128(9):522-8
references: 17697702
references: J Appl Physiol (1985). 2006 Jan;100(1):178-85
references: 16166239
references: Circulation. 2001 Mar 6;103(9):1245-9
references: 11238268
references: Clin Sci (Lond). 2014 Dec;127(11):645-54
references: 24947434
references: Biochem Biophys Res Commun. 2001 Jan 26;280(3):908-13
references: 11162610
references: Eur J Cancer. 2004 Dec;40(18):2829-36
references: 15571967
references: Mech Ageing Dev. 2003 Jul;124(7):811-7
references: 12875744
references: J Diabetes Res. 2013;2013:185172
references: 23671856
references: Ther Adv Cardiovasc Dis. 2009 Oct;3(5):347-56
references: 19723834
references: Neurosci Lett. 2010 Aug 9;480(1):1-3
references: 20074616
references: Cancer Res. 2007 Jul 15;67(14):6745-52
references: 17638885
references: Circulation. 2003 Jan 7;107(1):139-46
references: 12515756
references: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3251-6
references: 12626749
references: Age (Dordr). 2013 Feb;35(1):117-28
references: 22102320
references: J Cell Mol Med. 2005 Jan-Mar;9(1):153-9
references: 15784173
references: Life Sci. 2006 Apr 25;78(22):2615-24
references: 16318863
references: Hypertension. 2000 Jan;35(1 Pt 1):108-12
references: 10642283
references: Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1789-95
references: 18599796
references: Biochem Biophys Res Commun. 2004 Nov 26;324(4):1204-9
references: 15504342
references: Cardiovasc Res. 2005 May 1;66(2):286-94
references: 15820197
references: J Physiol. 2014 Jun 15;592(12):2549-61
references: 24665093
references: Acta Physiol Scand. 1999 Jul;166(3):203-8
references: 10468656
references: Clin Sci (Lond). 2011 Jun;120(11):485-91
references: 21143196
references: Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2301-9
references: 20798379
references: Science. 2006 Jun 16;312(5780):1650-3
references: 16728594
references: Curr Med Chem. 2006;13(9):989-96
references: 16611080
references: Free Radic Biol Med. 1998 Jun;24(9):1477-84
references: 9641266
references: Biochemistry. 2001 Apr 17;40(15):4763-8
references: 11294644
references: Circulation. 2012 Jul 24;126(4):468-78
references: 22705887
references: J Thorac Cardiovasc Surg. 2010 May;139(5):1286-94, 1294.e1-2
references: 19931095
references: Life Sci. 2005 Oct 7;77(21):2676-89
references: 15964597
references: J Cell Sci. 2007 Aug 1;120(Pt 15):2479-87
references: 17646672
references: Science. 2006 May 19;312(5776):1059-63
references: 16645051
references: J Appl Physiol (1985). 2011 Nov;111(5):1416-21
references: 21903879
references: Am J Physiol Heart Circ Physiol. 2013 Jul 15;305(2):H251-8
references: 23666675
references: J Gerontol A Biol Sci Med Sci. 2010 Jun;65(6):580-9
references: 20083554
references: Cell Metab. 2005 Jan;1(1):15-25
references: 16054041
references: Aging Cell. 2003 Oct;2(5):277-85
references: 14570235
references: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3404-14
references: 17906108
references: J Physiol. 2003 Feb 15;547(Pt 1):309-16
references: 12562958
references: J Physiol. 2009 Jul 1;587(Pt 13):3271-85
references: 19417091
references: Rinsho Byori. 2004 Dec;52(12):961-5
references: 15675341
references: Trends Endocrinol Metab. 2007 Nov;18(9):356-64
references: 17964799
references: Neurobiol Aging. 2012 May;33(5):1005.e23-35
references: 22071124
references: Aging Cell. 2011 Apr;10(2):220-32
references: 21108734
references: Science. 2004 Jul 16;305(5682):390-2
references: 15205477
references: Oncogene. 2005 Jul 28;24(32):5026-42
references: 15897889
references: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):890-5
references: 11792849
references: J Exp Med. 2000 Dec 18;192(12):1731-44
references: 11120770
references: PLoS One. 2012;7(4):e35312
references: 22514726
references: Mol Cell Biol. 1999 Mar;19(3):2109-17
references: 10022898
references: J Atheroscler Thromb. 2010 Sep 30;17(9):970-9
references: 20644332
references: Circulation. 1997 Jul 1;96(1):308-15
references: 9236450
references: Circulation. 2004 Nov 2;110(18):2889-95
references: 15505103
references: Hypertension. 2001 Feb;37(2 Pt 2):414-8
references: 11230310
references: EMBO J. 2003 Aug 15;22(16):4212-22
references: 12912919
references: J Gerontol A Biol Sci Med Sci. 2011 Apr;66(4):409-18
references: 21303813
references: Am J Physiol Heart Circ Physiol. 2013 Nov 15;305(10):H1417-27
references: 24043248
references: Atherosclerosis. 1996 Aug 23;125(1):47-51
references: 8831926
references: Hypertension. 1981 May-Jun;3(3 Pt 2):I148-53
references: 7262977
references: FEBS Lett. 2008 Jan 9;582(1):46-53
references: 18036349
references: Biochem Biophys Res Commun. 1993 Sep 15;195(2):1070-6
references: 7690550
references: Curr Biol. 1999 Sep 9;9(17):939-45
references: 10508581
references: Vasc Cell. 2012 Aug 28;4(1):12
references: 22929066
references: Handb Exp Pharmacol. 2006;(176 Pt 2):43-78
references: 16999224
references: Immunol Cell Biol. 2010 Oct;88(7):754-60
references: 20404837
references: Mol Cell Biol. 2007 May;27(9):3542-55
references: 17339337
references: Hypertension. 2006 Jun;47(6):1183-8
references: 16636195
references: Clin Sci (Lond). 2009 Apr;116(8):607-20
references: 19275766
references: Aging Cell. 2013 Oct;12(5):772-83
references: 23714110
references: Diabetes. 2006 Jul;55(7):2001-14
references: 16804069
references: Clin Sci (Lond). 2013 Mar;124(5):325-31
references: 23025811
references: Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H1025-32
references: 21622824
references: J Appl Physiol (1985). 2011 May;110(5):1171-80
references: 21233343
references: Circ Res. 2008 Jan 4;102(1):16-31
references: 18174472