title: Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone.
abstract: The brain possesses two intricate mechanisms that fulfill its continuous metabolic needs: cerebral autoregulation, which ensures constant cerebral blood flow over a wide range of arterial pressures and functional hyperemia, which ensures rapid delivery of oxygen and glucose to active neurons. Over the past decade, a number of important studies have identified astrocytes as key intermediaries in neurovascular coupling (NVC), the mechanism by which active neurons signal blood vessels to change their diameter. Activity-dependent increases in astrocytic Ca(2+) activity are thought to contribute to the release of vasoactive substances that facilitate arteriole vasodilation. A number of vasoactive signals have been identified and their role on vessel caliber assessed both in vitro and in vivo. In this review, we discuss mechanisms implicating astrocytes in NVC-mediated vascular responses, limitations encountered as a result of the challenges in maintaining all the constituents of the neurovascular unit intact and deliberate current controversial findings disputing a main role for astrocytes in NVC. Finally, we briefly discuss the potential role of pericytes and microglia in NVC-mediated processes.
authors.affiliation: Georgia Regents University, 1120 15th Street, Augusta, GA 30912, United States. Electronic address: jfilosa@gru.edu.
authors.forename: J A
authors.initials: JA
authors.lastname: Filosa
authors.affiliation: University of Arizona, 1305 N. Martin Avenue, P.O. Box 210203, Tucson, AZ 85721, United States.
authors.forename: H W
authors.initials: HW
authors.lastname: Morrison
authors.affiliation: Georgia Regents University, 1120 15th Street, Augusta, GA 30912, United States.
authors.forename: J A
authors.initials: JA
authors.lastname: Iddings
authors.affiliation: Georgia Regents University, 1120 15th Street, Augusta, GA 30912, United States.
authors.forename: W
authors.initials: W
authors.lastname: Du
authors.affiliation: Georgia Regents University, 1120 15th Street, Augusta, GA 30912, United States.
authors.forename: K J
authors.initials: KJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D017628:Microglia / Q000502:physiology; D000069336:Neurovascular Coupling / Q000502:physiology*; D020286:Pericytes / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
keywords: astrocyte; calcium; cerebral blood flow; myogenic tone; neurovascular coupling
references.citation: Glia. 2008 Jun;56(8):821-35
references.pmid: 18338793
references.citation: Acta Neuropathol. 2010 Jan;119(1):7-35
references.pmid: 20012068
references.citation: J Physiol. 2004 Aug 15;559(Pt 1):3-15
references.pmid: 15218071
references.citation: J Neurosci. 2006 Jun 28;26(26):6997-7006
references.pmid: 16807329
references.citation: Clin Exp Pharmacol Physiol. 2008 Sep;35(9):1116-20
references.pmid: 18215190
references.citation: Exp Brain Res. 2010 Dec;207(3-4):249-58
references.pmid: 20972776
references.citation: Glia. 1999 Jun;26(4):280-90
references.pmid: 10383047
references.citation: J Cereb Blood Flow Metab. 2010 Apr;30(4):808-15
references.pmid: 19920844
references.citation: J Cereb Blood Flow Metab. 2011 Mar;31(3):795-806
references.pmid: 21139630
references.citation: Am J Physiol Cell Physiol. 2010 Nov;299(5):C1068-78
references.pmid: 20844244
references.citation: Stroke. 2009 Apr;40(4):1451-7
references.pmid: 19246694
references.citation: ASN Neuro. 2012 Mar 22;4(2):
references.pmid: 22313347
references.citation: Prog Brain Res. 2004;145:171-8
references.pmid: 14650915
references.citation: J Chem Neuroanat. 2012 Oct;45(1-2):45-9
references.pmid: 22813698
references.citation: Brain Res Rev. 2010 May;63(1-2):138-48
references.pmid: 19948187
references.citation: Intravital. 2012;1(2):95-106
references.pmid: 24078900
references.citation: J Neurosci. 2013 May 8;33(19):8411-22
references.pmid: 23658179
references.citation: J Neurosci. 2008 May 7;28(19):4967-73
references.pmid: 18463250
references.citation: Am J Physiol. 1990 Sep;259(3 Pt 2):H902-8
references.pmid: 2168682
references.citation: Glia. 2011 Nov;59(11):1744-53
references.pmid: 21800362
references.citation: Br J Pharmacol. 2004 Feb;141(4):580-5
references.pmid: 14744815
references.citation: Stroke. 1996 May;27(5):971-9
references.pmid: 8623121
references.citation: Am J Physiol Renal Physiol. 2002 Jun;282(6):F1097-102
references.pmid: 11997326
references.citation: Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H622-32
references.pmid: 18055520
references.citation: Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H373-81
references.pmid: 21602473
references.citation: Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H74-80
references.pmid: 12623781
references.citation: Am J Physiol Cell Physiol. 2007 Sep;293(3):C1103-11
references.pmid: 17670890
references.citation: Nat Neurosci. 2007 Nov;10(11):1387-94
references.pmid: 17965659
references.citation: J Neurochem. 2004 Dec;91(5):1171-9
references.pmid: 15569260
references.citation: Am J Physiol Heart Circ Physiol. 2012 Jun 1;302(11):H2257-66
references.pmid: 22467311
references.citation: J Neurosci. 2003 Oct 8;23(27):9254-62
references.pmid: 14534260
references.citation: J Neurosci. 2007 Jun 6;27(23):6268-72
references.pmid: 17554000
references.citation: J Physiol. 2004 Dec 15;561(Pt 3):671-83
references.pmid: 15486015
references.citation: Neural Plast. 2013;2013:425845
references.pmid: 24392228
references.citation: Nature. 2010 Nov 25;468(7323):557-61
references.pmid: 20944627
references.citation: News Physiol Sci. 2002 Feb;17:27-31
references.pmid: 11821533
references.citation: Glia. 2015 May;63(5):795-811
references.pmid: 25643695
references.citation: Brain Res. 1999 Mar 13;821(2):368-73
references.pmid: 10064823
references.citation: Nat Neurosci. 1998 Aug;1(4):263-5
references.pmid: 10195155
references.citation: Am J Physiol Heart Circ Physiol. 2002 Nov;283(5):H2029-37
references.pmid: 12384482
references.citation: Glia. 2004 Apr 15;46(2):195-206
references.pmid: 15042586
references.citation: Glia. 2002 Mar 1;37(3):229-40
references.pmid: 11857681
references.citation: Circ Res. 2002 Oct 4;91(7):610-7
references.pmid: 12364389
references.citation: J Appl Physiol (1985). 2006 Mar;100(3):1059-64
references.pmid: 16467392
references.citation: Science. 1987 Aug 21;237(4817):896-8
references.pmid: 3616619
references.citation: Neuroscience. 1996 Oct;74(3):927-34
references.pmid: 8884787
references.citation: J Physiol. 2005 May 1;564(Pt 3):737-49
references.pmid: 15731184
references.citation: Vasc Cell. 2013 Feb 19;5(1):4
references.pmid: 23422217
references.citation: J Neuroinflammation. 2013 Jan 11;10:4
references.pmid: 23311642
references.citation: Glia. 1998 May;23(1):1-10
references.pmid: 9562180
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22290-5
references.pmid: 21135230
references.citation: Nat Rev Neurosci. 2004 May;5(5):347-60
references.pmid: 15100718
references.citation: Stroke. 1999 Dec;30(12):2727-34; discussion 2734
references.pmid: 10583004
references.citation: Nature. 2006 Oct 12;443(7112):700-4
references.pmid: 17036005
references.citation: Science. 1990 Jan 26;247(4941):470-3
references.pmid: 1967852
references.citation: Microvasc Res. 2001 Sep;62(2):196-203
references.pmid: 11516249
references.citation: Nature. 2010 Nov 11;468(7321):232-43
references.pmid: 21068832
references.citation: Brain Res. 2002 Nov 29;956(2):183-93
references.pmid: 12445685
references.citation: Microsc Res Tech. 2001 Apr 15;53(2):106-18
references.pmid: 11301486
references.citation: J Physiol. 2003 Dec 1;553(Pt 2):407-14
references.pmid: 14500777
references.citation: Front Neuroenergetics. 2010 Jun 23;2:9
references.pmid: 20616884
references.citation: Am J Physiol Heart Circ Physiol. 2001 May;280(5):H2011-22
references.pmid: 11299201
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):18974-9
references.pmid: 23112168
references.citation: Neuroscience. 1990;39(1):151-70
references.pmid: 2089275
references.citation: J Neurosci. 2009 Apr 1;29(13):3974-80
references.pmid: 19339593
references.citation: J Neurophysiol. 2015 Sep;114(3):1353-6
references.pmid: 25376788
references.citation: Nat Neurosci. 2006 Feb;9(2):260-7
references.pmid: 16388306
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2563-8
references.pmid: 21262839
references.citation: J Cell Biol. 2001 Apr 30;153(3):543-53
references.pmid: 11331305
references.citation: Cardiovasc Res. 1996 Oct;32(4):687-98
references.pmid: 8915187
references.citation: J Neurosci. 2003 Jun 1;23(11):4737-45
references.pmid: 12805313
references.citation: J Physiol. 1996 Apr 15;492 ( Pt 2):419-30
references.pmid: 9019539
references.citation: J Physiol Paris. 2012 Jan;106(1-2):34-9
references.pmid: 21979115
references.citation: J Gen Physiol. 2008 May;131(5):i2
references.pmid: 18443356
references.citation: J Neurosci Res. 1991 Feb;28(2):236-43
references.pmid: 2033652
references.citation: Glia. 2013 Jan;61(1):24-36
references.pmid: 22829357
references.citation: Nature. 2014 Apr 3;508(7494):55-60
references.pmid: 24670647
references.citation: Microvasc Res. 1999 Nov;58(3):312-28
references.pmid: 10527772
references.citation: Nature. 2004 Sep 9;431(7005):195-9
references.pmid: 15356633
references.citation: Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1073-9
references.pmid: 12666665
references.citation: J Neurosci. 2003 Nov 12;23(32):10302-10
references.pmid: 14614089
references.citation: Protein Cell. 2013 Apr;4(4):299-309
references.pmid: 23549615
references.citation: J Physiol. 2003 Sep 15;551(Pt 3):787-99
references.pmid: 12876212
references.citation: Front Neuroenergetics. 2010 Aug 16;2:
references.pmid: 20802803
references.citation: Antioxid Redox Signal. 2009 Feb;11(2):251-66
references.pmid: 18831678
references.citation: J Biol Chem. 2008 Nov 14;283(46):31284-8
references.pmid: 18826956
references.citation: Neuroscience. 2007 Sep 21;148(4):876-92
references.pmid: 17719182
references.citation: Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1369-77
references.pmid: 21803949
references.citation: Brain Res. 2001 Jul 13;907(1-2):93-9
references.pmid: 11430889
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):E197-205
references.pmid: 22167804
references.citation: Am J Physiol. 1997 Jan;272(1 Pt 2):H256-62
references.pmid: 9038945
references.citation: Curr Top Dev Biol. 2007;79:75-97
references.pmid: 17498548
references.citation: Brain Res. 1997 Apr 18;754(1-2):35-45
references.pmid: 9134957
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6157-62
references.pmid: 23530219
references.citation: Nature. 2008 Dec 11;456(7223):745-9
references.pmid: 18971930
references.citation: J Cereb Blood Flow Metab. 2013 Apr;33(4):479-82
references.pmid: 23385200
references.citation: Circ Res. 2001 Feb 2;88(2):132-3
references.pmid: 11157662
references.citation: Nature. 2005 Dec 15;438(7070):1017-21
references.pmid: 16355225
references.citation: J Neurosci. 2007 Apr 18;27(16):4452-9
references.pmid: 17442830
references.citation: J Cell Physiol. 2009 Mar;218(3):612-22
references.pmid: 19016245
references.citation: J Neuroinflammation. 2013 Aug 27;10:108
references.pmid: 23981568
references.citation: J Neurosci. 2013 Jun 12;33(24):10143-53
references.pmid: 23761909
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5163-8
references.pmid: 17360345
references.citation: Nat Neurosci. 2006 Nov;9(11):1397-1403
references.pmid: 17013381
references.citation: Glia. 2010 Jul;58(9):1094-103
references.pmid: 20468051
references.citation: Circ Res. 2005 Dec 9;97(12):e104-14
references.pmid: 16293786
references.citation: J Biol Chem. 2014 May 23;289(21):14470-80
references.pmid: 24737318
references.citation: J Appl Physiol (1985). 2006 Mar;100(3):1065-76
references.pmid: 16467393
references.citation: Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):1966-75
references.pmid: 16778120
references.citation: J Cereb Blood Flow Metab. 2010 Apr;30(4):757-68
references.pmid: 20040927
references.citation: J Neurosci. 2014 Sep 24;34(39):13139-50
references.pmid: 25253859
references.citation: Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H428-33
references.pmid: 21572018
references.citation: J Cereb Blood Flow Metab. 2011 Oct;31(10):2096-105
references.pmid: 21610722
references.citation: Circ J. 2010 Apr;74(4):608-16
references.pmid: 20234102
references.citation: Glia. 2013 Dec;61(12):2023-37
references.pmid: 24123492
references.citation: Cell. 2007 Dec 14;131(6):1164-78
references.pmid: 18083105
references.citation: Am J Physiol. 1999 Aug;277(2):H799-811
references.pmid: 10444508
references.citation: Ann N Y Acad Sci. 2012 Jul;1259:10-8
references.pmid: 22758631
references.citation: J Neurosci. 2002 Jan 1;22(1):183-92
references.pmid: 11756501
references.citation: J Gen Physiol. 2013 May;141(5):633-47
references.pmid: 23589582
references.citation: Am J Physiol Heart Circ Physiol. 2003 Nov;285(5):H2054-63
references.pmid: 12881223
references.citation: Brain Lang. 2007 Aug;102(2):141-52
references.pmid: 17010421
references.citation: Trends Neurosci. 2009 Mar;32(3):160-9
references.pmid: 19162338
references.citation: Cereb Cortex. 2005 Jul;15(7):938-49
references.pmid: 15483047
references.citation: Front Syst Neurosci. 2009 Sep 08;3:9
references.pmid: 19826613
references.citation: Trends Neurosci. 2005 Apr;28(4):188-95
references.pmid: 15808353
references.citation: Science. 2008 Jun 20;320(5883):1597-9
references.pmid: 18566273
references.citation: J Cereb Blood Flow Metab. 2008 Jan;28(1):111-25
references.pmid: 17519974
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3811-6
references.pmid: 20133576
references.citation: J Cereb Blood Flow Metab. 2004 Jul;24(7):744-55
references.pmid: 15241182
references.citation: Peptides. 2001 Jun;22(6):995-1007
references.pmid: 11390030
references.citation: Am J Physiol. 1999 Dec;277(6):R1760-70
references.pmid: 10600924
references.citation: Nature. 2003 Dec 4;426(6966):517-24
references.pmid: 14654832
references.citation: Nat Neurosci. 2003 Jan;6(1):43-50
references.pmid: 12469126
references.citation: J Physiol. 2012 Apr 1;590(7):1757-70
references.pmid: 22310311
references.citation: Nat Neurosci. 2011 Dec 11;15(1):70-80
references.pmid: 22158513
references.citation: J Neurosci. 2010 Sep 29;30(39):13116-29
references.pmid: 20881130
references.citation: Nat Neurosci. 2007 Nov;10(11):1369-76
references.pmid: 17965657
references.citation: Am J Physiol Heart Circ Physiol. 2000 Jul;279(1):H339-50
references.pmid: 10899074
references.citation: FASEB J. 1993 Aug;7(11):1031-8
references.pmid: 8370472
references.citation: J Neurosci. 2000 Sep 15;20(18):6968-73
references.pmid: 10995841
references.citation: J Vasc Res. 2012;49(5):375-89
references.pmid: 22739136
references.citation: PLoS Biol. 2010 Nov 02;8(11):e1000527
references.pmid: 21072242
references.citation: Glia. 2006 Apr 15;53(6):660-8
references.pmid: 16498631
references.citation: Nat Neurosci. 2005 Jun;8(6):752-8
references.pmid: 15895084
references.citation: Science. 2013 Jan 11;339(6116):197-200
references.pmid: 23307741
references.citation: J Neurochem. 2004 Jan;88(1):246-56
references.pmid: 14675168
references.citation: J Neurosci. 2002 Nov 1;22(21):9430-44
references.pmid: 12417668
references.citation: Circ Res. 2004 Nov 12;95(10):e73-81
references.pmid: 15499024
references.citation: Stroke. 2002 Nov;33(11):2692-9
references.pmid: 12411663
references.citation: Life Sci. 2011 Aug 1;89(5-6):141-6
references.pmid: 21684291
references.citation: J Cereb Blood Flow Metab. 2015 Jul;35(7):1127-36
references.pmid: 25757753
references.citation: J Gen Physiol. 2006 Dec;128(6):659-69
references.pmid: 17130519
references.citation: J Physiol. 2009 Apr 15;587(Pt 8):1639-47
references.pmid: 19204050
references.citation: Neuroscience. 2002;113(1):221-33
references.pmid: 12123700
references.citation: Cell Calcium. 2013 Aug;54(2):120-5
references.pmid: 23764169
references.citation: Nat Rev Neurosci. 2010 Feb;11(2):87-99
references.pmid: 20087359
references.citation: J Physiol. 2009 Feb 15;587(Pt 4):745-52
references.pmid: 19074968
references.citation: Nat Rev Immunol. 2011 Oct 25;11(11):775-87
references.pmid: 22025055
references.citation: Science. 1986 Jul 25;233(4762):453-4
references.pmid: 3726539
references.citation: Circ Res. 1972 Aug;31(2):240-7
references.pmid: 5049739
references.citation: Nature. 2010 Nov 25;468(7323):562-6
references.pmid: 20944625
references.citation: Am J Physiol Heart Circ Physiol. 2011 May;300(5):H1557-65
references.pmid: 21257913
references.citation: Neurochem Int. 2010 Dec;57(8):923-34
references.pmid: 20933035
references.citation: Am J Physiol Heart Circ Physiol. 2011 Jul;301(1):H1-H11
references.pmid: 21498777
references.citation: Vis Neurosci. 2001 Nov-Dec;18(6):935-40
references.pmid: 12020084
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17827-31
references.pmid: 22006332
references.citation: Trends Neurosci. 1999 May;22(5):208-15
references.pmid: 10322493
references.citation: Neuroscience. 2004;129(4):877-96
references.pmid: 15561405
references.citation: J Neurosci. 2006 Mar 15;26(11):2862-70
references.pmid: 16540563
references.citation: J Cereb Blood Flow Metab. 2014 Oct;34(10):1599-603
references.pmid: 25099754
references.citation: J Neurosci. 2007 Mar 7;27(10):2468-71
references.pmid: 17344384
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2855-63
references.pmid: 18456724
references.citation: Glia. 2007 Sep;55(12):1214-1221
references.pmid: 17659528
references.citation: Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):E4678-87
references.pmid: 24218625