Endothelial cells continuously respond to extracellular stimuli such as chemical signals produced by circulating blood elements or mechanical forces such as shear stress. Proinflammatory cytokines, mitogens, reactive oxygen species, and shear stress trigger signal molecules to initiate multiple intracellular pathways, which often converge at mitogen-activated protein (MAP) kinase activation. The MAP kinase superfamily represents a burgeoning area of clinical investigation for treatment of various inflammatory and oncologic diseases and plays an essential role in mediating response to infection, ischemia/reperfusion injury, and vessel healing and remodeling through regulation of such diverse phenomena as endothelial cell proliferation, migration, apoptosis, and endothelial barrier function. The downstream effects of MAP kinase activation include modulation of gene expression via up-regulation of various transcription factors. In addition to these sustained effects, MAP kinases coordinate more immediate responses that affect dynamic cytoskeletal rearrangements necessary for cell migration and regulation of barrier function. This review discusses the important regulatory roles of MAP kinases in the vital physiologic functions of endothelium, focusing mainly on the role of MAP kinases in the maintenance of endothelial barrier.
HerlaarE., BrownZ.p38 MAPK signaling cascades in inflammatory disease.Mol Med Today1999; 5: 439–47.
2.
JohnsonG.L., LapadatR.Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases.Science2002; 298: 1911–2.
3.
EnglishJ.M., CobbM.H.Pharmacological inhibitors of MAPK pathways.Trends Pharmacol Sci2002; 23: 40–5.
4.
Van den BlinkB., Ten HoveT., Van den BrinkG.R.From extracellular to intracellular targets, inhibiting MAP kinases in treatment of Crohn's disease.Ann N Y Acad Sci2002; 973: 349–58.
5.
DalrympleS.A.p38 Mitogen activated protein kinase as a therapeutic target for Alzheimer's disease.J Mol Neurosci2002; 19: 295–9.
6.
Obata X BrownG.E., YaffeM.B.MAP kinases pathways activated by stress: the p38 MAPK pathway.Crit Care Med2000; 28 Suppl: N67–77.
7.
ArbabiS., MaierR.V.Mitogen-activated protein kinases.Crit Care Med2002; 30: S74–9.
SchlessingerJ.Cell signaling by receptor tyrosine kinases.Cell2000; 103: 211–25.
10.
BerkB.C.Redox signals that regulate the vascular response to injury.Thromb Haemost1999; 82: 810–7.
11.
TeradaL.S.Oxidative stress and endothelial activation.Crit Care Med2002; 30: S186–91.
12.
GarciaJ.G.N., SchaphorstK.L., VerinA.D.Diperoxovanadate alters endothelial cell focal contacts and barrier function: role of tyrosine phosphorylation.I Appl Physiol2000; 89: 2333–43.
13.
NatarajanV., ScribnerW.M., MorrisA.J.Role of p38 MAP kinase in diperoxovanadate-induced phospholipase D activation in endothelial cells.Am J Physiol2001; 281: L435–49.
14.
KevilC., OshimaT., AlexanderB.H2O2-mediated permeability: role of MAPK and occludin.Am J Physiol2000; 279: C21–30.
15.
KevilC.G., OshimaT., AlexanderJ.S.The role of p38 MAP kinase in hydrogen peroxide mediated endothelial solute permeability.Endothelium2001; 8: 107–16.
16.
RobinsonC.J.M., SlossC.M., PlevinR.Inactivation of JNK activity by mitogen-activated protein kinase phosphatase-2 in EAhy296 endothelial cells is dependent upon agonist-specific JNK translocation to the nucleus.Cell Signal2001; 13: 29–41.
17.
HojoY., SaitoY., TanimotoT.Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathion-reducatse-mediated mechanism.Circ Res2002; 91: 712–8.
18.
LanderH.M., OgisteJ.S., TengK.K., NovogrodskyA.p21ras As a common signaling target of reactive free radicals and cellular redox stress.J Biol Chem1995, 270: 21195–8.
19.
GuytonK.Z., LiuY., GorospeM.Activation of mitogen-activated protein kinase by H2O2.J Biol Chem1996; 271: 4138–42.
20.
GotohY., CooperJ.A.Reactive oxygen species- and dimerization-induced activation of apoptosis signal-regulating kinase 1 in tumor necrosis factor-α signal transduction.J Biol Chem1998; 273: 17477–82.
21.
KennedyT.P., RaoN.V., HopkinsC.Role of reactive oxygen species in reperfusion injury of the rabbit lung.J Clin Invest1989; 83: 1326–35.
22.
VepaS., ScribnerW.M., ParinandiN.L.Hydrogen peroxide stimulates tyrosine phosphorylation of focal adhesion kinase in vascular endothelial cells.Am J Physiol1999; 277: L150–8.
CampbellD.H., SutherlandR.L., DalyR.J.Signaling pathways and structural domains required for phosphorylation of EMS1/cortactin.Cancer Res1999; 59: 5376–85.
25.
LiY., LiuJ., ZhanX.Tyrosine phosphorylation of cortactin is required for H2O2-mediated injury of human endothelial cells.J Biol Chem2000; 275: 37187–93.
26.
CordenonsiM., TurcoF., D'AtriF.Xenopus laevis occludin. Identification of in vitro phosphorylation sites by protein kinase CK2 and association with cingulin.Eur J Biochem1999; 264: 374–84.
27.
SayedM., KimS.O., SalhB.S.Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase.J Biol Chem2000; 275: 16569–73.
28.
GudmundsdottirI.J., HalldorsonH., MagnusdottirK., ThorgeirssonG.Involvement of MAP kinases in the control of cPLA2 and aracidonic acid release in endothelial cells.Atherosclerosis2001; 156: 81–90.
29.
DownwardJ., GravesJ.D., WarneP.H.Stimulation of p21ras uponT-cell activation.Nature1990; 346: 696–7.
30.
KazanietzM.G.Eyes wide shut: protein kinase C isozymes are not the only receptors for the phorbol ester tumor promoters.Mol Carcinog2000; 28: 5–11.
ChiloechesA., PatersonH.F., MaraisR.Regulation of Ras-GTP loading and Ras-Raf association in neonatal rat ventricular myocytes by G-protein-coupled receptor agonist and phorbol ester.J Biol Chem1999; 274: 19762–70.
33.
MaraisR., LightY., MasonC.Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C.Science1998; 280: 109–12.
34.
UedaY., HiraiS., OsadaS.Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf.J Biol Chem1996; 271: 23512–9.
35.
KolchW., HeideckerG., KochsG.Protein kinase C alpha activates RAF-1 by direct phosphorylation.Nature1993; 364: 249–52.
36.
StasekJ.E., PattersonC.E., GarciaJ.G.N.Protein kinase C phosphorylates caldesmon 77 and vimentin and enhances albumin permeability across cultured bovine pulmonary artery endothelial cell monolayers.J Cell Physiol1992; 153: 62–75.
37.
VerinA.D., LiuF., BogatchevaN.Role of Ras-dependent ERK activation in phorbol ester-induced endothelial cell barrier dysfunction.Am J Physiol2000; 279: L360–70.
38.
TakataM., UrakazeM., TemaruR.Pravastatin suppresses the interleukin-8 production induced by thrombin in human aortic endothelial cells cultured with high glucose by inhibiting the p42/44 mitogen activating protein kinase.Br J Pharmacol2001; 134: 753–62.
39.
HuangC.K., DevanneyJ.F., KennedyS.P.Vimentin, a cytoskeletal substrate of protein kinase C.Biochem Biophys Res Commun1988; 150: 1006–11.
40.
Ciesielski-TreskaJ., UlrichG., AunisD.Protein kinase C-induced redistribution of the cytoskeleton and phosphorylation of vimentin in cultured brain macrophages.J Neurosci Res1991; 29: 362–78.
41.
ChildsT.J., WatsonM.H., SangheraJ.S.Phosphorylation of smooth muscle caldesmon by mitogen-activated protein (MAP) kinase and expression of MAP kinase in differentiated smooth muscle cells.J Biol Chem1992; 267: 22853–9.
42.
UmekawaH., HidakaH.Phosphorylation of caldesmon by protein kinase C.Biochem Biophys Res Commun1985; 132: 56–62.
43.
HedgesJ.C., OxhornB.C., CartyM.Phosphorylation of caldesmon by ERK MAP kinases in smooth muscle.Am J Physiol2000; 278: C718–26.
44.
BelchevaM.M., CosciaC.J.Diversity of G protein-coupled receptor signaling pathways to ERK/MAP kinase.Neurosignals2002; 11: 34–44.
45.
BlaukatA., BaracA., CrossM.L.G protein-coupled receptor-mediated mitogen-activated protein kinase activation through cooperation of Gαq and Gαi signals.Mol Cell Biol2000; 20: 6837–48.
46.
CollinsL.R., MindenA., KarinM., BrownJ.H.Gα12 stimulates c-Jun NH2-terminal kinase through the small G proteins Ras and Rac.J Biol Chem1996; 271: 17349–53.
47.
PierceK.L., LuttrellL.M., LefkowitzR.J.New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades.Oncogene2001; 20: 1532–9.
48.
KaslowH.R., BurnsD.L.Pertussis toxin and target eukaryotic cells: binding, entry, and activation.FASEB J1992; 6: 2684–90.
49.
PattersonC.E., StasekJ.E., SchaphorstK.L.Mechanisms of pertussis toxin-induced barrier dysfunction in bovine pulmonary artery endothelial cells.Am J Physiol1995; 268: L926–34.
50.
GarciaJ.G.N., WangP., LiuF.Pertussis toxin directly activates endothelial cell p42/p44 MAP kinases via a novel signaling pathway.Am J Physiol2001; 280: 0233–41.
51.
GarciaJ.G.N., WangP., SchaphorstK.L.Critical involvement of p38 MAP kinase in pertussis toxin-induced cytoskeletal reorganization and lung permeability.FASEB J2002; 16: 1064–76.
52.
HedgesJ.C., YambolievI.A., NgoM.p38 Mitogen-activated protein kinase expression and activation in smooth muscle.Am J Physiol1998; 275: C527–34.
53.
YambolievI.A., HedgesJ.C., MutnickJ.L.-MEvidence for modulation of smooth muscle force by the p38 MAP kinase/hsp27 pathway.Am J Physiol2000; 278: H1899–907.
54.
GoncharovaE.A., VorotnikovA.V., GrachevaE.O.Activation of p38 MAP-kinase and caldesmon phosphorylation are essential for urokinase-induced human smooth muscle cell migration.Biol Chem2002; 383: 115–26.
55.
GusevN.B., BogatchevaN.V., MarstonS.B.Structure and properties of small heat shock proteins (sHsp) and their interaction with cytoskeleton proteins.Biochemistry (Mosc)2002; 67: 511–9.
56.
PiotrowiczR.S., LevinE.G.Basolateral membrane-associated 27-kDa heat shock protein and microfilament polymerization.J Biol Chem1999; 272: 25920–7.
57.
BenndorfR., HayessK., RyazantsevS.Phosphorylation and supramolecular organization of murine small heat shock protein hsp25 abolish its actin polymerization-inhibiting activity.J Biol Chem1994; 269: 20780–4.
58.
IbitayoAl, SladickJ., TutejaS.Hsp27 in signal transduction and association with contractile proteins in smooth muscle cells.Am J Physiol1999; 277: G445–54.
59.
HedgesJ.C., DechertM.A., YambolievI.A.A role for p38MAPK/HSP27 pathway in smooth muscle cell migration.J Biol Chem1999; 274: 24211–9.
FanY., WuD-Z, GongY-QMetabolic responses induced by thrombin in human umbilical vein endothelial cells.Biochem Biophys Res Commun2002; 293: 979–85.
64.
Wheeler-JonesC.P.D., MayM.J., MorganA.J., PearsonJ.D.Protein tyrosine kinase regulate agonist-stimulated prostacyclin release but not von Willebrand factor secretion from human umbilical vein endothelial cells.Biochem J1996; 315: 407–16.
65.
KeoghR.J., HoulistonR.A., Wheeler-JonesC.P.D.Thrombin-stimulated Pyk2 phosphorylation in human endothelium is dependent on intracellular calcium and independent of protein kinase C and Src kinases.Biochem Biophys Res Commun2002; 294: 1001–8.
66.
BlaukatA., Ivankovic-DikicI., GronroosE.Adaptor protein Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades.J Biol Chem1999; 274: 14893–901.
67.
RahmanA., AnwarK.N., UddinS.Protein kinase C-δ regulates thrombin-induced ICAM-1 gene expression in endothelial cells via activation of p38 mitogen-activated protein kinase.Mol Cell Biol2001; 21: 5554–65.
68.
Vouret-CraviariV., BoquetP., PouyssegurJ., Van Obberghen-SchillingE.Regulation of the actin cytoskeleton by thrombin in human endothelial cells: role of Rho proteins in endothelial barrier function.Mol Biol Cell1998; 9: 2639–53.
PanettiT.S.Differential effects of sphingosine 1-phosphate and lysophosphatidic acid on endothelial cells.Biochim Biophys Acta2002; 1582: 190–6.
71.
LeeO.H., KimY.M., LeeY.M.Sphingosine 1-phosphate induces angiogenesis: its angiogenic action and signaling mechanism in human umbilical vein endothelial cells.Biochem Biophys Res Commun1999; 264: 743–50.
72.
KimuraT., WatanabeT., SatoK.Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3.Biochem J2000; 348: 71–6.
73.
LiuF., VerinA.D., WangP.Differential regulation of sphingosine-1-phosphate- and VEGF-induced endothelial cell chemotaxis.Am J Respir Cell Mol Biol2001; 24: 711–9.
74.
IgarashiJ., BernierS.G., MichelT.Sphingosine 1-phosphate and activation of endothelial nitric-oxide synthase.J Biol Chem2001; 276: 12420–6.
75.
BannoY., TakuwaY., YamadaM.Involvement of phospholipase D in insulin-like growth factor-1-induced activation of extracellular signal-regulated kinase, but not phosphatidylinositol 3-kinase or Akt, in Chinese hamster ovary cells.Biochem J2003; 369: 363–368.
76.
WangL., CummingsR., UsatyukP.Involvement of phos-pholipases D1 and D2 in sphingosine 1-phosphate-induced ERK (extracellular-signal-regulated kinase) activation and interleukin-8 secretion in human bronchial epithelial cells.Biochem J2002; 367: 751–60.
77.
RousseauS., HouleF., LandryJ., HuotJ.p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells.Oncogene1997; 15: 2169–77.
78.
BeckerP.M., VerinA.D., BoothM.A.Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells.Am J Physiol2001; 281: L1500–11.
79.
GilleH., KowalskiJ., LiB.Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2).J Biol Chem2001; 276: 3222–30.
80.
D'AngeloG., MartiniJ-F, IiriT.16K human prolactin inhibits vascular endothelial growth factor-induced activation of Ras in capillary endothelial cells.Mol Endocrinol1999; 13: 692–704.
81.
TakahashiT., UenoH., ShibuyaM.VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells.Oncogene1999; 18: 2221–30.
LandgrenE., SchillerP., CaoY., Claesson-WelshL.Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-γ and migration of endothelial cells expressing Flt 1.Oncogene1998; 16: 359–67.
OshimaT., FloresS.C., VaiataitisG.HIV-1 Tat increases endothelial solute permeability through tyrosine kinase and mitogen-activated protein kinase-dependent pathway.AIDS2000; 14: 475–82.
LiuF., SchaphorstK.L., VerinA.D.Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: potential role of glycogen synthase kinase-3p.FASEB J2002; 16: 950–62.
88.
CaiW., RookS.L., JiangZ.Y.Mechanism of hepatocyte growth factor-induced retinal endothelial cell migration and growth.Invest Ophthalmol Vis Sci2000; 41: 1885–93.
89.
MaH., CalderonT.M., FallonJ.T., BermanJ.W.Hepatocyte growth factor is a survival factor for endothelial cells and is expressed in human atherosclerotic plaques.Atherosclerosis2002; 164: 79–87.
90.
ManganiniM., MaierJ.A.M.Transforming growth factor β2 inhibition of hepatocyte growth factor-induced endothelial proliferation and migration.Oncogene2000; 19: 124–33.
91.
RubinfeldB., AlbertI., PorfiriE.Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly.Science1996; 272: 1023–6.
92.
SethiJ.M., OtterbeinL.E., ChoiA.M.Differential modulation by exogenous carbon monoxide of TNF-alpha stimulated mitogen-activated protein kinases in rat pulmonary artery endothelial cells.Antioxid Redox Signal2002; 4: 241–8.
GenerschE., HayesK., NeuenfeldY., HallerH.Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras-dependent and -independent pathways.J Cell Sci2000; 113: 4319–30.
97.
PetracheI., VerinA.D., CrowM.T.Differential effect of MLC kinase in TNF-α-induced endothelial cell apoptosis and barrier dysfunction.Am J Physiol2001; 280: L1168–78.
98.
NwariakuF.E., ChangJ., ZhuX.The role of p38 map kinase in tumor necrosis factor-induced redistribution of vascular endothelial cadherin and increased endothelial permeability.Shock2002; 18: 82–5.
99.
FerreroE., ZocchiM.R., MagniE.Roles of tumor necrosis factor p55 and p75 receptors in TNF-α-induced vascular permeability.Am J Physiol2001; 281: 0173–9.
100.
KiemerA.K., WeberN.C., FurstR.Inhibition of p38 MAPK activation via induction of MKP-1.Circ Res2002; 90: 874–81.
101.
LiuY., MinW.Thioredoxin promotes ASK1 ubiquitination and degradation to inhibit ASK-dependent apoptosis in a redox activity-independent manner.Circ Res2002; 90: 1259–66.
102.
ChengN., ChenJ.Tumor necrosis factor-alpha induction of endothelial ephrin Al expression is mediated by a p38 MAPK- and SAPK/JNK-dependent but nuclear factor-kappa B-independent mechanism.J Biol Chem2001; 276: 13771–7.
103.
AliM.H., SchumackerP.T.Endothelial responses to mechanichal stress: where is the mechanosensor?Crit Care Med2002; 30: 198–206.
104.
TsengH., PetersonT.E., BerkB.C.Fluid shear stress stimulates mitogen-activated protein kinase in endothelial cells.Circ Res1995; 77: 869–78.
105.
JoH., SiposK., GoY.M.Differential effect of shear stress on extracellular signal-regulated kinase and N-terminal Jun kinase in endothelial cells.J Biol Chem1997; 272: 1395–401.
YehL.H., ParkY.J., HansaliaR.J.Shear-induced tyrosine phosphorylation in endothelial cells requires Racl-dependent production of ROS.Am J Physiol1999; 276: C838–47.
109.
TraubO., MoniaB.P., DeanN.M., BerkB.C.PKC-ε is required for mechanosensitive activation of ERK112 in endothelial cells.J Biol Chem1997; 272: 31251–7.
110.
LiS., ChenB.P.C., AzumaN.Distinct roles for the small GTPases Cdc42 and Rho in endothelial responses to shear stress.J Clin Invest1999; 103: 1141–50.
111.
GoY.M., BooY.C., ParkH.Protein kinase B/Akt activates c-Jun NH2-terminal kinase by increasing NO production in response to shear stress.I Appl Physiol2001; 91: 1574–81.
112.
GoY.M., ParkH., MalandM.C.Phosphatydylinositol 3-kinase γ mediates shear stress-dependent activation of JNK in endothelial cells.Am J Physiol1998; 275: H1898–904.
113.
Shay-SalitA., ShushyM., WolfovitzE.VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells.Proc Natl Acad Sci U S A2002; 99: 9462–7.
114.
BirukovK.G., BirukovaA.A., DudekS.M.Shear stress-mediated cytoskeletal remodeling and cortactin translocation in pulmonary endothelial cells.Am J Respir Cell Mol Biol2002; 26: 453–64.
115.
AzumaN., AkasakaN., KitoH.Role of p38 MAP kinase in endothelial cell alignment induced by fluid shear stress.Am J Physiol2001; 280: H189–97.
116.
UrbichC., DernbachE., ReissnerA.Shear stress-induced endothelial cell migration involves integrin signaling via the fibronectin receptor subunits α5 and β1.Arte-rioscler Thromb Vasc Biol2002; 22: 69–75.
117.
LevesqueM.J., NeremR.M., SpragueE.A.Vascular endothelial cell proliferation in culture and the influence of flow.Bio-materials1990; 11: 702–7.
