title: Vascular dysfunction associated with type 2 diabetes and Alzheimer's disease: a potential etiological linkage.
abstract: The endothelium performs a crucial role in maintaining vascular integrity leading to whole organ metabolic homeostasis. Endothelial dysfunction represents a key etiological factor leading to moderate to severe vasculopathies observed in both Type 2 diabetic and Alzheimer's Disease (AD) patients. Accordingly, evidence-based epidemiological factors support a compelling hypothesis stating that metabolic rundown encountered in Type 2 diabetes engenders severe cerebral vascular insufficiencies that are causally linked to long term neural degenerative processes in AD. Of mechanistic importance, Type 2 diabetes engenders an immunologically mediated chronic pro-inflammatory state involving interactive deleterious effects of leukocyte-derived cytokines and endothelial-derived chemotactic agents leading to vascular and whole organ dysfunction. The long term negative consequences of vascular pro-inflammatory processes on the integrity of CNS basal forebrain neuronal populations mediating complex cognitive functions establish a striking temporal comorbidity of AD with Type 2 diabetes. Extensive biomedical evidence supports the pivotal multi-functional role of constitutive nitric oxide (NO) production and release as a critical vasodilatory, anti-inflammatory, and anti-oxidant, mechanism within the vascular endothelium. Within this context, we currently review the functional contributions of dysregulated endothelial NO expression to the etiology and persistence of Type 2 diabetes-related and co morbid AD-related vasculopathies. Additionally, we provide up-to-date perspectives on critical areas of AD research with special reference to common NO-related etiological factors linking Type 2 diabetes to the pathogenesis of AD.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Nanjing Maternit and Child Health Care Hospital, Nanjing Medical University, Nanjing, China (mainland).
authors.forename: Fuzhou
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institutes of Pediatrics, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China (mainland).
authors.forename: Xirong
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China (mainland).
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Shen
authors.affiliation: Neuroscience Research Institute, State University of New York - College at Old Westbury, Old Westbury, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Kream
authors.affiliation: Neuroscience Research Institute, State University of New York - College at Old Westbury, Old Westbury, USA.
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Mantione
authors.affiliation: Neuroscience Research Institute, State University of New York - College at Old Westbury, Old Westbury, USA.
authors.forename: George B
authors.initials: GB
authors.lastname: Stefano
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D014652:Vascular Diseases / Q000150:complications* / Q000503:physiopathology*
references.citation: Nephrol Dial Transplant. 2006 Jan;21(1):51-7
references.pmid: 16204297
references.citation: Front Pharmacol. 2014 Apr 01;5:57
references.pmid: 24744731
references.citation: J Neuroinflammation. 2011 Mar 25;8:26
references.pmid: 21439035
references.citation: IUBMB Life. 2013 Oct;65(10):819-26
references.pmid: 24078390
references.citation: J Hepatol. 1999 Jun;30(6):1035-44
references.pmid: 10406181
references.citation: Eur J Biochem. 1995 Aug 15;232(1):188-91
references.pmid: 7556149
references.citation: J Periodontal Res. 2010 Apr;45(2):177-83
references.pmid: 20470258
references.citation: Vascul Pharmacol. 2014 Apr;61(1):16-24
references.pmid: 24548897
references.citation: Circulation. 1995 Dec 15;92(12):3505-12
references.pmid: 8521573
references.citation: Neurotox Res. 2009 Oct;16(3):293-305
references.pmid: 19526276
references.citation: FEBS Lett. 1999 Feb 5;444(1):75-7
references.pmid: 10037151
references.citation: Diabetes Metab Res Rev. 2015 Feb;31(2):113-26
references.pmid: 24845883
references.citation: Handb Exp Pharmacol. 2006;(176 Pt 1):213-54
references.pmid: 16999221
references.citation: Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E829-41
references.pmid: 19190261
references.citation: Diabetes. 2008 Dec;57(12):3307-14
references.pmid: 18835939
references.citation: Neurobiol Aging. 2009 Dec;30(12):1910-7
references.pmid: 18372080
references.citation: Circ Res. 1994 Dec;75(6):1086-95
references.pmid: 7525103
references.citation: Life Sci. 1995;57(2):103-12
references.pmid: 7603292
references.citation: Ann N Y Acad Sci. 1997 Sep 26;826:75-91
references.pmid: 9329682
references.citation: Atherosclerosis. 2013 Sep;230(1):131-9
references.pmid: 23958265
references.citation: FEBS Lett. 1997 Oct 6;415(3):341-5
references.pmid: 9357996
references.citation: Lancet. 2014 Mar 22;383(9922):1084-94
references.pmid: 24315621
references.citation: Eur J Pharmacol. 1986 Dec 2;132(1):75-8
references.pmid: 3816968
references.citation: Biochem Biophys Res Commun. 1996 Jan 5;218(1):40-4
references.pmid: 8573169
references.citation: J Alzheimers Dis. 2009;16(4):859-64
references.pmid: 19387118
references.citation: Gerontology. 1997;43(1-2):26-43
references.pmid: 8996828
references.citation: Diabetes. 1997 Jun;46(6):1040-6
references.pmid: 9166677
references.citation: J Basic Clin Physiol Pharmacol. 2014 Jan 27;:1-9
references.pmid: 24468620
references.citation: J Biol Chem. 2002 Jun 21;277(25):22402-6
references.pmid: 11950842
references.citation: JAMA. 2011 Jun 22;305(24):2556-64
references.pmid: 21693744
references.citation: Recent Prog Horm Res. 1998;53:43-59; discussion 59-60
references.pmid: 9769702
references.citation: Circ Res. 2010 Apr 30;106(8):1319-31
references.pmid: 20431074
references.citation: J Biol Chem. 1999 May 21;274(21):14692-8
references.pmid: 10329664
references.citation: J Huazhong Univ Sci Technolog Med Sci. 2009 Dec;29(6):684-8
references.pmid: 20037807
references.citation: Brain Res Brain Res Rev. 2000 Dec;34(3):119-36
references.pmid: 11113503
references.citation: J Biol Chem. 1992 Dec 15;267(35):24929-32
references.pmid: 1281150
references.citation: Front Physiol. 2014 May 06;5:175
references.pmid: 24834056
references.citation: Neurol Res. 2003 Sep;25(6):635-41
references.pmid: 14503018
references.citation: J Interferon Cytokine Res. 2014 Nov;34(11):839-47
references.pmid: 24831467
references.citation: Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37
references.pmid: 8944624
references.citation: Nitric Oxide. 2011 Oct 30;25(3):255-64
references.pmid: 21820072
references.citation: Curr Vasc Pharmacol. 2011 Mar;9(2):136-44
references.pmid: 21143171
references.citation: Arch Biochem Biophys. 1991 Aug 15;289(1):130-6
references.pmid: 1654842
references.citation: J Mol Cell Cardiol. 1998 May;30(5):979-88
references.pmid: 9618238
references.citation: Free Radic Biol Med. 1998 Sep;25(4-5):434-56
references.pmid: 9741580
references.citation: PLoS One. 2014 Apr 02;9(4):e93433
references.pmid: 24695675
references.citation: Am Heart J. 2014 Apr;167(4):421-8
references.pmid: 24655688
references.citation: Chem Res Toxicol. 2012 May 21;25(5):975-89
references.pmid: 22449080
references.citation: Curr Med Chem. 2005;12(10):1161-208
references.pmid: 15892631
references.citation: FEBS Lett. 1994 Dec 19;356(2-3):295-8
references.pmid: 7805858
references.citation: Free Radic Biol Med. 1998 Sep;25(4-5):404-33
references.pmid: 9741579
references.citation: Invest Ophthalmol Vis Sci. 1991 Jan;32(1):53-64
references.pmid: 1702773
references.citation: Neurol Res. 2001 Jul;23(5):506-12
references.pmid: 11474807
references.citation: Int J Cardiol. 2014 Jun 15;174(2):230-42
references.pmid: 24794552
references.citation: Circ Res. 1998 Feb 23;82(3):346-59
references.pmid: 9486663
references.citation: Recent Pat Cardiovasc Drug Discov. 2011 Sep;6(3):222-41
references.pmid: 21906026
references.citation: Proc Natl Acad Sci U S A. 1989 Jul;86(13):5141-5
references.pmid: 2740348
references.citation: J Clin Diagn Res. 2014 Mar;8(3):108-10
references.pmid: 24783095
references.citation: Acta Neuropathol. 1999 Jul;98(1):1-8
references.pmid: 10412794
references.citation: Res Commun Chem Pathol Pharmacol. 1990 Apr;68(1):13-25
references.pmid: 2161118
references.citation: Chin Med J (Engl). 2008 Feb 5;121(3):241-7
references.pmid: 18298918
references.citation: J Pharmacol Exp Ther. 1997 Oct;283(1):138-47
references.pmid: 9336318
references.citation: N Engl J Med. 1989 Apr 20;320(16):1025-30
references.pmid: 2927481
references.citation: Arch Biochem Biophys. 2009 Apr 15;484(2):214-20
references.pmid: 19159609
references.citation: Nitric Oxide. 1998;2(1):37-44
references.pmid: 9706741
references.citation: Cardiovasc Diabetol. 2011 Jun 02;10:48
references.pmid: 21635764
references.citation: Exp Gerontol. 2011 Apr;46(4):225-32
references.pmid: 21112383
references.citation: Neurol Res. 1992;14(2 Suppl):177-80
references.pmid: 1355882
references.citation: Brain Res. 1992 Jun 12;582(2):186-95
references.pmid: 1327402
references.citation: Biochim Biophys Acta. 1999 May 5;1411(2-3):378-84
references.pmid: 10320670
references.citation: Cell Mol Biol (Noisy-le-grand). 2005 Sep 30;51(4):371-6
references.pmid: 16309587
references.citation: J Neurosci Res. 2012 Oct;90(10):1989-96
references.pmid: 22714978
references.citation: Saudi J Ophthalmol. 2011 Apr;25(2):113-22
references.pmid: 23960912
references.citation: Am J Gastroenterol. 2001 Jul;96(7):2129-36
references.pmid: 11467644
references.citation: Am J Physiol Heart Circ Physiol. 2012 Dec 1;303(11):H1283-93
references.pmid: 23023869
references.citation: Pharmacol Ther. 2013 Feb;137(2):133-52
references.pmid: 23026155
references.citation: J Neurosci Res. 1995 Jun 1;41(2):238-45
references.pmid: 7650759
references.citation: Cell Mol Life Sci. 1997 Jul;53(7):576-82
references.pmid: 9312403
references.citation: Circ Res. 2009 May 22;104(10):1178-83
references.pmid: 19407240
references.citation: J Cardiovasc Pharmacol. 2010 Apr;55(4):300-7
references.pmid: 20422734
references.citation: Biochim Biophys Acta. 1999 May 5;1411(2-3):351-69
references.pmid: 10320668
references.citation: J Am Coll Cardiol. 2013 Jan 15;61(2):148-52
references.pmid: 23219296
references.citation: Am J Physiol. 1997 Aug;273(2 Pt 1):G530-6
references.pmid: 9277434
references.citation: Lancet. 2010 Feb 27;375(9716):735-42
references.pmid: 20167359
references.citation: J Biol Chem. 1996 Feb 23;271(8):4209-14
references.pmid: 8626764
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2013 Mar;386(3):217-26
references.pmid: 23254361
references.citation: Circ Res. 1998 Jun 29;82(12):1263-71
references.pmid: 9648722
references.citation: Eur J Pharmacol. 2005 Mar 21;511(1):53-64
references.pmid: 15777779
references.citation: J Alzheimers Dis. 2014;40(3):619-30
references.pmid: 24503617
references.citation: Ann Thorac Surg. 1997 Apr;63(4):1063-9
references.pmid: 9124906
references.citation: Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H1982-8
references.pmid: 18790831
references.citation: Exp Diabetes Res. 2012;2012:618923
references.pmid: 23197974
references.citation: Free Radic Biol Med. 2014 Aug;73:174-89
references.pmid: 24816293
references.citation: Curr Vasc Pharmacol. 2012 Jan;10(1):4-18
references.pmid: 22112350
references.citation: Eur J Pharmacol. 1993 Feb 23;232(1):29-34
references.pmid: 8458394
references.citation: Br Med Bull. 1994 Oct;50(4):776-88
references.pmid: 7804730
references.citation: Biochem Biophys Res Commun. 2004 Mar 5;315(2):509-16
references.pmid: 14766238
references.citation: J Biochem. 2010 Mar;147(3):297-306
references.pmid: 20068028
references.citation: Life Sci. 1987 Feb 16;40(7):643-8
references.pmid: 3807653
references.citation: J Cereb Blood Flow Metab. 2009 Mar;29(3):621-8
references.pmid: 19107135
references.citation: J Neuropathol Exp Neurol. 2003 Dec;62(12):1287-301
references.pmid: 14692704
references.citation: Br J Pharmacol. 2009 Nov;158(6):1527-35
references.pmid: 19845678
references.citation: Eur J Biochem. 1994 May 1;221(3):1033-7
references.pmid: 8181459
references.citation: Cardiorenal Med. 2013 Dec;3(4):265-82
references.pmid: 24474955
references.citation: J Diabetes Complications. 2005 Mar-Apr;19(2):101-6
references.pmid: 15745840
references.citation: Phys Ther. 2008 Nov;88(11):1322-35
references.pmid: 18801863
references.citation: Clin Exp Pharmacol Physiol. 2010 Apr;37(4):429-34
references.pmid: 19843095
references.citation: Cell Rep. 2014 Apr 10;7(1):223-35
references.pmid: 24703845
references.citation: Endocrinology. 2009 May;150(5):2098-108
references.pmid: 19106228
references.citation: Blood Vessels. 1988;25(5):250-60
references.pmid: 3167224
references.citation: Med Sci Monit. 2011 Oct;17(10):RA221-6
references.pmid: 21959625
references.citation: Am J Physiol Cell Physiol. 2013 Nov 15;305(10):C1033-40
references.pmid: 23986204
references.citation: Lancet Neurol. 2004 Mar;3(3):184-90
references.pmid: 14980533
references.citation: Neurol Res. 1993 Jun;15(3):146-53
references.pmid: 8103579
references.citation: Acta Pharmacol Sin. 2002 Feb;23(2):97-102
references.pmid: 11866867
references.citation: Cardiovasc Res. 2005 Oct 1;68(1):26-36
references.pmid: 16009356
references.citation: Neurosci Lett. 1997 Feb 28;223(3):165-8
references.pmid: 9080458
references.citation: Biochem Biophys Res Commun. 1994 Oct 14;204(1):169-75
references.pmid: 7945356
references.citation: J Appl Physiol (1985). 1994 Mar;76(3):1166-71
references.pmid: 7516323
references.citation: Neurol Res. 2004 Jul;26(5):517-24
references.pmid: 15265269
references.citation: Toxicology. 2005 Mar 15;208(2):305-17
references.pmid: 15691594
references.citation: J Alzheimers Dis. 2009;16(4):845-58
references.pmid: 19387117
references.citation: FEBS Lett. 1994 May 23;345(1):50-4
references.pmid: 8194600
references.citation: Methods Enzymol. 2008;437:287-310
references.pmid: 18433634
references.citation: Am J Physiol Endocrinol Metab. 2009 May;296(5):E1029-41
references.pmid: 19208858
references.citation: Adv Exp Med Biol. 2009;645:193-8
references.pmid: 19227471
references.citation: J Biol Chem. 1999 Apr 2;274(14):9427-30
references.pmid: 10092623
references.citation: Glia. 2005 Dec;52(4):276-88
references.pmid: 16001426
references.citation: Diabetes. 1993 Jul;42(7):1017-25
references.pmid: 8513969
references.citation: Cardiovasc Toxicol. 2011 Jun;11(2):134-47
references.pmid: 21360312
references.citation: Diabetes. 2012 Jun;61(6):1573-83
references.pmid: 22438576
references.citation: Antioxid Redox Signal. 2010 Apr;12(4):537-77
references.pmid: 19650713
references.citation: Prog Neurobiol. 2000 Apr;60(6):513-30
references.pmid: 10739087
references.citation: Arch Biochem Biophys. 1995 Oct 20;323(1):27-32
references.pmid: 7487069
references.citation: J Alzheimers Dis. 2014;38(1):75-83
references.pmid: 23948922
references.citation: Am J Physiol Endocrinol Metab. 2014 Mar;306(6):E648-57
references.pmid: 24425765
references.citation: J Alzheimers Dis. 2013;35(3):623-35
references.pmid: 23478310
references.citation: Curr Neurovasc Res. 2013 Feb;10(1):76-80
references.pmid: 23151073
references.citation: Curr Med Chem. 2014;21(19):2208-17
references.pmid: 24372221
references.citation: Exp Biol Med (Maywood). 2009 Sep;234(9):1020-8
references.pmid: 19546350
references.citation: Front Physiol. 2013 Dec 13;4:347
references.pmid: 24379783
references.citation: Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2524-31
references.pmid: 17885213
references.citation: Inorg Chem. 2010 Jul 19;49(14):6293-316
references.pmid: 20666388
references.citation: Biochim Biophys Acta. 1999 May 5;1411(2-3):334-50
references.pmid: 10320667
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8807-11
references.pmid: 8090728