title: Blood cells and endothelial barrier function.
abstract: The barrier properties of endothelial cells are critical for the maintenance of water and protein balance between the intravascular and extravascular compartments. An impairment of endothelial barrier function has been implicated in the genesis and/or progression of a variety of pathological conditions, including pulmonary edema, ischemic stroke, neurodegenerative disorders, angioedema, sepsis and cancer. The altered barrier function in these conditions is often linked to the release of soluble mediators from resident cells (e.g., mast cells, macrophages) and/or recruited blood cells. The interaction of the mediators with receptors expressed on the surface of endothelial cells diminishes barrier function either by altering the expression of adhesive proteins in the inter-endothelial junctions, by altering the organization of the cytoskeleton, or both. Reactive oxygen species (ROS), proteolytic enzymes (e.g., matrix metalloproteinase, elastase), oncostatin M, and VEGF are part of a long list of mediators that have been implicated in endothelial barrier failure. In this review, we address the role of blood borne cells, including, neutrophils, lymphocytes, monocytes, and platelets, in the regulation of endothelial barrier function in health and disease. Attention is also devoted to new targets for therapeutic intervention in disease states with morbidity and mortality related to endothelial barrier dysfunction.
authors.affiliation: Department of Clinical and Toxicological Analyses; School of Pharmaceutical Sciences; University of Sao Paulo ; Sao Paulo, Brazil.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Rodrigues
authors.affiliation: Department of Molecular and Cellular Physiology; Louisiana State University Health Sciences Center ; Shreveport, LA USA.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
keywords: AJ, Adherens junctions; ANG-1, Angiopoietin 1; AQP, Aquaporins; BBB, blood brain barrier; CNS, Central nervous system; COPD, Chronic obstructive pulmonary disease; EAE, Experimental autoimmune encephalomyelitis; EPAC1, Exchange protein activated by cyclic AMP; ERK1/2, Extracellular signal-regulated kinases 1 and 2; Endothelial barrier; FA, Focal adhesions; FAK, focal adhesion tyrosine kinase; FoxO1, Forkhead box O1; GAG, Glycosaminoglycans; GDNF, Glial cell-derived neurotrophic factor; GJ, Gap junctions; GPCR, G-protein coupled receptors; GTPase, Guanosine 5'-triphosphatase; HMGB-1, High mobility group box 1; HRAS, Harvey rat sarcoma viral oncogene homolog; ICAM-1, Intercellular adhesion molecule 1; IL-1β, Interleukin 1 beta; IP3, Inositol 1,4,5-triphosphate; JAM, Junctional adhesion molecules; MEK, Mitogen-activated protein kinase kinase; MLC, Myosin light chain; MLCK, Myosin light-chain kinase; MMP, Matrix metalloproteinases; NO, Nitric oxide; OSM, Oncostatin M; PAF, Platelet activating factor; PDE, Phosphodiesterase; PKA, Protein kinase A; PNA, Platelet-neutrophil aggregates; ROS, Reactive oxygen species; Rac1, Ras-related C3 botulinum toxin substrate 1; Rap1, Ras-related protein 1; RhoA, Ras homolog gene family, member A; S1P, Sphingosine-1-phosphate; SCID, Severe combined immunodeficient; SOCS-3, Suppressors of cytokine signaling 3; Shp-2, Src homology 2 domain-containing phosphatase 2; Src, Sarcoma family of protein kinases; TEER, Transendothelial electrical resistance; TGF-beta1, Transforming growth factor-beta1; TJ, Tight junctions; TNF-, Tumor necrosis factor alpha; VCAM-1, Vascular cell adhesion molecule 1; VE, Vascular endothelial; VE-PTP, Vascular endothelial receptor protein tyrosine phosphatase; VEGF, Vascular endothelial growth factor; VVO, Vesiculo-vacuolar organelle; ZO, Zonula occludens; cAMP, 3'-5'-cyclic adenosine monophosphate; erythrocytes; leukocytes; pSrc, Phosphorylated Src; platelets; vascular permeability
references.citation: Cardiovasc Res. 2009 Jul 1;83(1):24-33
references.pmid: 19297368
references.citation: Am J Physiol. 1990 Aug;259(2 Pt 2):H390-4
references.pmid: 2167021
references.citation: Microcirculation. 2010 Apr;17(3):192-205
references.pmid: 20374483
references.citation: Epilepsia. 2012 Nov;53 Suppl 6:7-13
references.pmid: 23134490
references.citation: Am J Physiol. 1988 Dec;255(6 Pt 2):H1269-75
references.pmid: 3059826
references.citation: Blood. 2006 Feb 1;107(3):940-6
references.pmid: 16204319
references.citation: Nat Immunol. 2014 Mar;15(3):223-30
references.pmid: 24487320
references.citation: J Cell Physiol. 2014 Jul;229(7):916-26
references.pmid: 24318462
references.citation: Cardiovasc Res. 2010 Jul 15;87(2):291-9
references.pmid: 20299333
references.citation: Curr Rheumatol Rep. 2014 Jan;16(1):388
references.pmid: 24258615
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H2745-53
references.pmid: 17259442
references.citation: PLoS One. 2008 Aug 22;3(8):e3037
references.pmid: 18725947
references.citation: Int Rev Cytol. 2006;248:261-98
references.pmid: 16487793
references.citation: Virulence. 2013 Aug 15;4(6):543-55
references.pmid: 23924893
references.citation: J Surg Res. 1997 Apr;69(1):11-3
references.pmid: 9202640
references.citation: J Biol Chem. 2004 Mar 5;279(10 ):8886-94
references.pmid: 14684744
references.citation: Nat Cell Biol. 2008 Aug;10(8):883-5
references.pmid: 18670447
references.citation: Circ Res. 2010 Jun 11;106(11):1731-42
references.pmid: 20413783
references.citation: Rev Endocr Metab Disord. 2013 Mar;14(1):39-48
references.pmid: 23417760
references.citation: Cell Tissue Res. 2009 Jan;335(1):17-25
references.pmid: 18855014
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12493-8
references.pmid: 16891410
references.citation: Curr Cancer Drug Targets. 2005 Dec;5(8):629-43
references.pmid: 16375667
references.citation: J Cell Biol. 2002 Apr 1;157(1):149-60
references.pmid: 11927607
references.citation: J Thorac Cardiovasc Surg. 2009 Mar;137(3):695-702; discussion 702
references.pmid: 19258091
references.citation: Annu Rev Biomed Eng. 2007;9:121-67
references.pmid: 17373886
references.citation: Cytokine. 2011 Jul;55(1):24-8
references.pmid: 21482134
references.citation: Chem Immunol Allergy. 2014;99:216-25
references.pmid: 24217612
references.citation: Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H394-401
references.pmid: 14512275
references.citation: J Cell Biol. 1986 Apr;102(4):1304-11
references.pmid: 3007533
references.citation: J Biol Chem. 2000 Feb 25;275(8):5983-6
references.pmid: 10681592
references.citation: Brain. 2008 Apr;131(Pt 4):1087-98
references.pmid: 18267965
references.citation: Microcirculation. 2002 Apr;9(2):99-109
references.pmid: 11932777
references.citation: Annu Rev Physiol. 2011;73:283-309
references.pmid: 20936941
references.citation: Circ Res. 2006 Mar 17;98(5):675-81
references.pmid: 16469954
references.citation: J Physiol. 2005 Oct 1;568(Pt 1):123-35
references.pmid: 16020454
references.citation: J Neurochem. 2000 Aug;75(2):563-75
references.pmid: 10899931
references.citation: J Appl Physiol (1985). 2004 Sep;97(3):1152-8
references.pmid: 15169746
references.citation: J Pharmacol Exp Ther. 1975 Dec;195(3):549-56
references.pmid: 172625
references.citation: J Cell Biol. 2013 Apr 29;201(3):449-65
references.pmid: 23629967
references.citation: Nature. 2011 Jun 08;475(7355):222-5
references.pmid: 21654748
references.citation: J Cell Sci. 2013 Aug 15;126(Pt 16):3756-69
references.pmid: 23750010
references.citation: Stroke. 2011 Nov;42(11):3323-8
references.pmid: 21940972
references.citation: Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):394-400
references.pmid: 19122172
references.citation: Cytopathology. 2005 Aug;16(4):193-8
references.pmid: 16048505
references.citation: J Cereb Blood Flow Metab. 2011 Mar;31(3):819-31
references.pmid: 20877385
references.citation: Am J Physiol. 1992 Aug;263(2 Pt 2):H641-6
references.pmid: 1510161
references.citation: J Am Soc Nephrol. 2007 Nov;18(11):2885-93
references.pmid: 17942961
references.citation: Microcirculation. 2001 Jun;8(3):141-2
references.pmid: 11498777
references.citation: PLoS One. 2012;7(7):e41932
references.pmid: 22860034
references.citation: J Immunol. 2012 Aug 15;189(4):1937-45
references.pmid: 22772449
references.citation: J Neurochem. 2004 Apr;89(2):503-13
references.pmid: 15056293
references.citation: Mol Immunol. 1999 Dec;36(17):1175-88
references.pmid: 10698320
references.citation: J Immunol. 1993 Sep 15;151(6):3267-73
references.pmid: 7690799
references.citation: Exp Cell Res. 2007 Jul 1;313(11):2504-20
references.pmid: 17493609
references.citation: Mol Biol Cell. 2000 Dec;11(12):4131-42
references.pmid: 11102513
references.citation: J Virol. 2005 Aug;79(16):10442-50
references.pmid: 16051836
references.citation: J Thorac Imaging. 1998 Apr;13(2):128-34
references.pmid: 9556290
references.citation: Am J Physiol. 1997 Dec;273(6 Pt 1):G1189-99
references.pmid: 9435543
references.citation: Br J Cancer. 2002 Sep 9;87(6):621-3
references.pmid: 12237771
references.citation: Circ Res. 1997 Oct;81(4):618-26
references.pmid: 9314844
references.citation: Biochem Biophys Res Commun. 1989 Aug 15;162(3):1431-7
references.pmid: 2788411
references.citation: Pharmacol Rep. 2008 Jan-Feb;60(1):68-74
references.pmid: 18276987
references.citation: J Appl Physiol (1985). 2001 Oct;91(4):1487-500
references.pmid: 11568129
references.citation: Microvasc Res. 2009 May;77(3):340-7
references.pmid: 19323971
references.citation: PLoS One. 2008 Feb 20;3(2):e1649
references.pmid: 18297135
references.citation: Glia. 2003 Jun;42(4):433-46
references.pmid: 12730964
references.citation: Physiol Rev. 2008 Apr;88(2):451-87
references.pmid: 18391170
references.citation: Curr Pharm Des. 2012;18(25):3731-4
references.pmid: 22574986
references.citation: J Clin Invest. 2009 Jul;119(7):1871-9
references.pmid: 19603543
references.citation: J Cell Sci. 2008 Jul 1;121(Pt 13):2115-22
references.pmid: 18565824
references.citation: Trends Cell Biol. 2010 Feb;20(2):92-101
references.pmid: 19944606
references.citation: J Biol Chem. 2009 Feb 20;284(8):5381-94
references.pmid: 19095647
references.citation: Neuromolecular Med. 2010 Jun;12(2):193-204
references.pmid: 19579016
references.citation: BMJ. 1995 Sep 16;311(7007):731-3
references.pmid: 7549690
references.citation: Mol Imaging. 2008 Nov-Dec;7(6):248-62
references.pmid: 19123995
references.citation: Am J Physiol. 1995 Aug;269(2 Pt 1):L248-60
references.pmid: 7544537
references.citation: Physiol Rev. 2010 Oct;90(4):1337-81
references.pmid: 20959618
references.citation: Minerva Med. 2013 Jun;104(3):333-47
references.pmid: 23748287
references.citation: Cold Spring Harb Perspect Biol. 2010 Jan;2(1):a002907
references.pmid: 20182608
references.citation: J Allergy Clin Immunol. 1992 Apr;89(4):905-15
references.pmid: 1560171
references.citation: Am J Physiol. 1994 Oct;267(4 Pt 2):H1329-36
references.pmid: 7943378
references.citation: J Cereb Blood Flow Metab. 2014 Mar;34(3):433-40
references.pmid: 24346691
references.citation: Crit Rev Microbiol. 2004;30(3):187-96
references.pmid: 15490970
references.citation: J Biol Chem. 2009 Sep 18;284(38):25602-11
references.pmid: 19633358
references.citation: Crit Care. 2013 Oct 07;17(5):R226
references.pmid: 24099563
references.citation: Thromb Res. 1984 Aug 15;35(4):421-30
references.pmid: 6484891
references.citation: Dev Cell. 2009 Feb;16(2):209-21
references.pmid: 19217423
references.citation: Physiol Rev. 1999 Jul;79(3):703-61
references.pmid: 10390517
references.citation: J Biol Chem. 2000 Jul 7;275(27):20520-6
references.pmid: 10877843
references.citation: Thromb Haemost. 2007 Nov;98(5):944-51
references.pmid: 18000597
references.citation: Ann Allergy Asthma Immunol. 2014 May;112(5):413-8
references.pmid: 24484972
references.citation: Mol Cell Biol. 2012 Aug;32(15):2979-91
references.pmid: 22645303
references.citation: Prog Mol Biol Transl Sci. 2013;116:119-44
references.pmid: 23481193
references.citation: Fluids Barriers CNS. 2012 Nov 09;9(1):23
references.pmid: 23140302
references.citation: J Cell Biol. 1998 Jul 13;142(1):117-27
references.pmid: 9660867
references.citation: Circ Res. 2010 Oct 15;107(8):943-52
references.pmid: 20947863
references.citation: Physiol Rev. 2003 Oct;83(4):1359-400
references.pmid: 14506308
references.citation: Cell Regul. 1991 Feb;2(2):105-20
references.pmid: 1650581
references.citation: J Physiol. 2001 May 1;532(Pt 3):785-91
references.pmid: 11313446
references.citation: Ann Chir Gynaecol. 1980;69(5):178-90
references.pmid: 6162412
references.citation: Br J Pharmacol. 2012 May;166(2):434-46
references.pmid: 22145651
references.citation: Am J Physiol Cell Physiol. 2003 Aug;285(2):C343-52
references.pmid: 12700137
references.citation: Microvasc Res. 1989 May;37(3):256-66
references.pmid: 2733598
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L434-42
references.pmid: 12740216
references.citation: Curr Med Chem. 2014;21(19):2130-7
references.pmid: 24372215
references.citation: Am J Physiol. 1992 Mar;262(3 Pt 2):H771-7
references.pmid: 1558187
references.citation: Neurosurg Focus. 2007 May 15;22(5):E4
references.pmid: 17613235
references.citation: Brain Res. 2009 Dec 8;1301:152-62
references.pmid: 19748495
references.citation: Cell. 1996 Feb 9;84(3):345-57
references.pmid: 8608588
references.citation: Dev Cell. 2012 Jan 17;22(1):146-57
references.pmid: 22264731
references.citation: J Neuropathol Exp Neurol. 2001 Nov;60(11):1087-98
references.pmid: 11706938
references.citation: Am J Physiol. 1996 Dec;271(6 Pt 2):H2254-62
references.pmid: 8997281
references.citation: J Cereb Blood Flow Metab. 2012 Jul;32(7):1139-51
references.pmid: 22252235
references.citation: Am J Physiol. 1962 Nov;203:775-81
references.pmid: 13953498
references.citation: Cardiovasc Res. 2011 Dec 1;92 (3):456-65
references.pmid: 21908648
references.citation: FASEB J. 2007 Apr;21(4):1202-9
references.pmid: 17215483
references.citation: Am J Physiol. 1992 Feb;262(2 Pt 2):H611-5
references.pmid: 1539722
references.citation: Neurochem Res. 2012 Feb;37(2):401-9
references.pmid: 22002662
references.citation: Blood. 2005 Mar 1;105(5):1950-5
references.pmid: 15374886
references.citation: Expert Rev Mol Med. 2009 Jun 30;11:e19
references.pmid: 19563700
references.citation: J Cell Biol. 2003 May 12;161(3):653-60
references.pmid: 12743111
references.citation: Free Radic Biol Med. 2012 Feb 1;52(3):556-92
references.pmid: 22154653
references.citation: J Pathol. 2000 Feb;190(3):255-66
references.pmid: 10685060
references.citation: Cold Spring Harb Perspect Biol. 2009 Aug;1(2):a002584
references.pmid: 20066090
references.citation: Nat Med. 2000 Apr;6(4):460-3
references.pmid: 10742156
references.citation: Neurobiol Aging. 2014 Jun;35(6):1286-92
references.pmid: 24485508
references.citation: Neurobiol Dis. 2010 Jan;37(1):13-25
references.pmid: 19664713
references.citation: Trends Immunol. 2009 Nov;30(11):547-56
references.pmid: 19783480
references.citation: Circ Res. 2002 Nov 15;91(10):877-87
references.pmid: 12433832
references.citation: J Clin Invest. 2004 Mar;113(6):885-94
references.pmid: 15067321
references.citation: Front Biosci. 2007 Jan 01;12:2412-24
references.pmid: 17127251
references.citation: Blood. 2013 Oct 3;122(14):2512-22
references.pmid: 23908467
references.citation: Nature. 2012 May 23;485(7399):451-2
references.pmid: 22622564
references.citation: Physiol Rev. 2006 Jan;86(1):279-367
references.pmid: 16371600
references.citation: Cardiovasc Res. 2008 Jan;77(1):160-8
references.pmid: 18006475
references.citation: Microvasc Res. 2009 Jan;77(1):26-34
references.pmid: 19041330
references.citation: Blood. 2012 Aug 9;120(6):1334-43
references.pmid: 22544703
references.citation: Biochem J. 2009 Apr 15;419(2):261-72
references.pmid: 19309313
references.citation: J Thromb Haemost. 2011 Jul;9 Suppl 1:56-65
references.pmid: 21781242
references.citation: Arterioscler Thromb Vasc Biol. 2010 Dec;30(12 ):2392-9
references.pmid: 21071696
references.citation: Circ Res. 2007 Feb 2;100(2):246-54
references.pmid: 17218602
references.citation: Mol Biol Cell. 2009 Jan;20(1):33-42
references.pmid: 18923147
references.citation: Crit Care Med. 2014 Jul;42(7):e525-33
references.pmid: 24674922
references.citation: J Cell Biol. 1993 Dec;123(6 Pt 2):1777-88
references.pmid: 8276896
references.citation: Nat Cell Biol. 2008 Aug;10 (8):923-34
references.pmid: 18604199
references.citation: Blood. 1975 Oct;46(4):567-78
references.pmid: 1174690
references.citation: Ann N Y Acad Sci. 2012 Sep;1268:26-34
references.pmid: 22994218
references.citation: Annu Rev Biochem. 1996;65:475-502
references.pmid: 8811187
references.citation: Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651-5
references.pmid: 1675786
references.citation: Thromb Haemost. 2015 Jan;113(1):20-36
references.pmid: 25183310
references.citation: Gastroenterology. 1983 May;84(5 Pt 1):1035-49
references.pmid: 6339310
references.citation: Curr Pharm Des. 2013;19(1):17-28
references.pmid: 22950505
references.citation: PLoS One. 2014 Mar 19;9(3):e91597
references.pmid: 24646764
references.citation: Transfusion. 2008 Oct;48(10):2060-8
references.pmid: 18564388
references.citation: Histochem Cell Biol. 2012 Dec;138(6):861-79
references.pmid: 22886143
references.citation: Neurosci Lett. 2008 Aug 22;441(2):163-6
references.pmid: 18603369
references.citation: Nature. 2010 Nov 25;468(7323):557-61
references.pmid: 20944627
references.citation: Cell Mol Neurobiol. 2004 Jun;24(3):491-7
references.pmid: 15206827
references.citation: Lymphat Res Biol. 2013 Sep;11(3):128-35
references.pmid: 24024573
references.citation: J Cell Sci. 2002 May 1;115(Pt 9):1837-46
references.pmid: 11956315
references.citation: Proc Natl Acad Sci U S A. 1976 May;73(5):1612-6
references.pmid: 179091
references.citation: Mol Neurodegener. 2011 Mar 22;6:23
references.pmid: 21426580
references.citation: J Biol Chem. 1999 Aug 13;274(33):23463-7
references.pmid: 10438525
references.citation: Am J Physiol Heart Circ Physiol. 2012 Oct 1;303(7):H825-34
references.pmid: 22865384
references.citation: Science. 2010 Apr 30;328(5978):562-4
references.pmid: 20430990
references.citation: Compr Physiol. 2012 Oct;2(4):2471-80
references.pmid: 23720254
references.citation: Neurobiol Dis. 2004 Jun;16(1):1-13
references.pmid: 15207256
references.citation: Curr Opin Virol. 2014 Aug;7:134-40
references.pmid: 25063986
references.citation: J Physiol. 2012 Mar 1;590(5):1023-34
references.pmid: 22183721
references.citation: World J Gastroenterol. 2010 Dec 14;16(46):5790-800
references.pmid: 21154999
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Jul;285(1):L258-67
references.pmid: 12626332
references.citation: Circ Res. 1994 Mar;74(3):376-82
references.pmid: 8118946
references.citation: Histochem Cell Biol. 2002 Feb;117(2):105-12
references.pmid: 11935286
references.citation: J Cell Biol. 1995 Apr;129(1):203-17
references.pmid: 7698986
references.citation: Nature. 1969 Apr 5;222(5188):33-6
references.pmid: 5775827
references.citation: J Leukoc Biol. 1990 Mar;47(3):234-43
references.pmid: 2307906
references.citation: Adv Exp Med Biol. 2010;661:155-67
references.pmid: 20204729
references.citation: J Biol Chem. 2003 Apr 18;278(16):14002-12
references.pmid: 12584200
references.citation: Am J Physiol. 1998 Jun;274(6 Pt 2):H1885-94
references.pmid: 9841516
references.citation: Biochem Pharmacol. 1990 Jan 1;39(1):75-84
references.pmid: 2153383
references.citation: J Vasc Res. 2002 Sep-Oct;39(5):375-90
references.pmid: 12297701
references.citation: Virulence. 2013 Aug 15;4(6):525-36
references.pmid: 23841977
references.citation: Immune Netw. 2013 Jun;13(3):102-6
references.pmid: 23885224
references.citation: Cardiovasc Res. 2010 Jul 15;87(2):272-80
references.pmid: 20479130
references.citation: Am J Respir Crit Care Med. 2002 Jun 15;165(12 ):1634-9
references.pmid: 12070065
references.citation: J Neuroinflammation. 2013 Dec 01;10:142
references.pmid: 24289502