Abstract
cAMP is one of the most potent signaling molecules to stabilize the endothelial barrier, both under resting conditions as well as under challenge of barrier-destabilizing mediators. The two main signaling axes downstream of cAMP are activation of protein kinase A (PKA) as well as engagement of exchange protein directly activated by cAMP (Epac) and its effector GTPase Rap1. Interestingly, both pathways activate GTP exchange factors for Rac1, such as Tiam1 and Vav2 and stabilize the endothelial barrier via Rac1-mediated enforcement of adherens junctions and strengthening of the cortical actin cytoskeleton. On the level of Rac1, cAMP signaling converges with other barrier-enhancing signaling cues induced by sphingosine-1-phosphate (S1P) and angiopoietin-1 (Ang1) rendering Rac1 as an important signaling hub. Moreover, activation of Rap1 and inhibition of RhoA also contribute to barrier stabilization, emphasizing that regulation of small GTPases is a central mechanism in this context. The relevance of cAMP/Rac1-mediated barrier protection under pathophysiologic conditions can be concluded from data showing that inflammatory mediators causing multi-organ failure in systemic inflammation or sepsis interfere with this signaling axis on the level of cAMP or Rac1. This is in line with the well-known efficacy of cAMP to abrogate the barrier breakdown in response to most barrier-compromising stimuli. New is the notion that the tight endothelial barrier under resting conditions is maintained by (1) continuous cAMP formation induced by hormones such as epinephrine or (2) by activation of Rac1 downstream of S1P that is secreted by erythrocytes and activated platelets.
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References
Adamson RH, Liu B, Fry GN, Rubin LL, Curry FE (1998) Microvascular permeability and number of tight junctions are modulated by cAMP. Am J Physiol 274:H1885–H1894
Adamson RH, Zeng M, Adamson GN, Lenz JF, Curry FE (2003) PAF- and bradykinin-induced hyperpermeability of rat venules is independent of actin-myosin contraction. Am J Physiol Heart Circ Physiol 285:H406–H417
Adamson RH, Ly JC, Sarai RK, Lenz JF, Altangerel A, Drenckhahn D, Curry FE (2008) Epac/Rap1 pathway regulates microvascular hyperpermeability induced by PAF in rat mesentery. Am J Physiol Heart Circ Physiol 294:H1188–H1196
Adamson RH, Sarai RK, Altangerel A, Thirkill TL, Clark JF, Curry F-RE (2012a) Sphingosine-1-phosphate modulation of basal permeability and acute inflammatory responses in rat venular microvessels. Cardiovasc Res 88(2):344–351
Adamson RH, Sarai RK, Clark JF, Altangerel A, Thirkill TL, Curry FE (2012b) Attenuation by sphingosine-1-phosphate of rat microvessel acute permeability response to bradykinin is rapidly reversible. Am J Physiol Heart Circ Physiol 302(10):H1929–H1935
Aslam M, Schluter KD, Rohrbach S, Rafiq A, Nazli S, Piper HM, Noll T, Schulz R, Gunduz D (2013) Hypoxia-reoxygenation-induced endothelial barrier failure: role of RhoA, Rac1 and myosin light chain kinase. J Physiol 591:461–473
Baumer Y, Drenckhahn D, Waschke J (2008) cAMP induced Rac 1-mediated cytoskeletal reorganization in microvascular endothelium. Histochem Cell Biol 129:765–778
Baumer Y, Spindler V, Werthmann RC, Bünemann M, Waschke J (2009) Role of Rac 1 and cAMP in endothelial barrier stabilization and thrombin-induced barrier breakdown. J Cell Physiol 220(3):716–726
Birukova AA, Alekseeva E, Mikaelyan A, Birukov KG (2007a) HGF attenuates thrombin-induced endothelial permeability by Tiam1-mediated activation of the Rac pathway and by Tiam1/Rac-dependent inhibition of the Rho pathway. FASEB J 21:2776–2786
Birukova AA, Chatchavalvanich S, Oskolkova O, Bochkov VN, Birukov KG (2007b) Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection. Microvasc Res 73:173–181
Birukova AA, Malyukova I, Mikaelyan A, Fu P, Birukov KG (2007c) Tiam1 and betaPIX mediate Rac-dependent endothelial barrier protective response to oxidized phospholipids. J Cell Physiol 211:608–617
Birukova AA, Malyukova I, Poroyko V, Birukov KG (2007d) Paxillin-beta-catenin interactions are involved in Rac/Cdc42-mediated endothelial barrier-protective response to oxidized phospholipids. Am J Physiol Lung Cell Mol Physiol 293(1):L199–L211
Birukova AA, Zagranichnaya T, Fu P, Alekseeva E, Chen W, Jacobson JR, Birukov KG (2007e) Prostaglandins PGE(2) and PGI(2) promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation. Exp Cell Res 313:2504–2520
Birukova AA, Alekseeva E, Cokic I, Turner CE, Birukov KG (2008a) Cross talk between paxillin and Rac is critical for mediation of barrier-protective effects by oxidized phospholipids. Am J Physiol Lung Cell Mol Physiol 295(4):L593–L602
Birukova AA, Zagranichnaya T, Alekseeva E, Bokoch GM, Birukov KG (2008b) Epac/Rap and PKA are novel mechanisms of ANP-induced Rac-mediated pulmonary endothelial barrier protection. J Cell Physiol 215:715–724
Birukova AA, Cokic I, Moldobaeva N, Birukov KG (2009) Paxillin is involved in the differential regulation of endothelial barrier by HGF and VEGF. Am J Respir Cell Mol Biol 40(1):99–107
Birukova AA, Burdette D, Moldobaeva N, Xing J, Fu P, Birukov KG (2010) Rac GTPase is a hub for protein kinase A and Epac signaling in endothelial barrier protection by cAMP. Microvasc Res 79:128–138
Birukova AA, Zebda N, Cokic I, Fu P, Wu T, Dubrovskyi O, Birukov KG (2011a) p190RhoGAP mediates protective effects of oxidized phospholipids in the models of ventilator-induced lung injury. Exp Cell Res 317:859–872
Birukova AA, Zebda N, Fu P, Poroyko V, Cokic I, Birukov KG (2011b) Association between adherens junctions and tight junctions via Rap1 promotes barrier protective effects of oxidized phospholipids. J Cell Physiol 226:2052–2062
Birukova AA, Starosta V, Tian X, Higginbotham K, Koroniak L, Berliner JA, Birukov KG (2013a) Fragmented oxidation products define barrier disruptive endothelial cell response to OxPAPC. Transl Res 161:495–504
Birukova AA, Tian X, Tian Y, Higginbotham K, Birukov KG (2013b) Rap-afadin axis in control of Rho signaling and endothelial barrier recovery. Mol Biol Cell 24:2678–2688
Birukova AA, Wu T, Tian Y, Meliton A, Sarich N, Tian X, Leff A, Birukov KG (2013c) Iloprost improves endothelial barrier function in lipopolysaccharide-induced lung injury. Eur Respir J 41:165–176
Camerer E, Regard JB, Cornelissen I, Srinivasan Y, Duong DN, Palmer D, Pham TH, Wong JS, Pappu R, Coughlin SR (2009) Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J Clin Invest 119:1871–1879
Cioffi DL, Moore TM, Schaack J, Creighton JR, Cooper DM, Stevens T (2002) Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase. J Cell Biol 157:1267–1278
Cullere X, Shaw SK, Andersson L, Hirahashi J, Luscinskas FW, Mayadas TN (2005) Regulation of vascular endothelial barrier function by Epac, a cAMP-activated exchange factor for Rap GTPase. Blood 105:1950–1955
Curry FR, Adamson RH (2010) Vascular permeability modulation at the cell, microvessel, or whole organ level: towards closing gaps in our knowledge. Cardiovasc Res 87:218–229
Curry FR, Adamson RH (2013) Tonic regulation of vascular permeability. Acta Physiol (Oxf) 207:628–649
Curry FE, Zeng M, Adamson RH (2003) Thrombin increases permeability only in venules exposed to inflammatory conditions. Am J Physiol Heart Circ Physiol 285:H2446–H2453
Curry FE, Clark JF, Adamson RH (2012) Erythrocyte-derived sphingosine-1-phosphate stabilizes basal hydraulic conductivity and solute permeability in rat microvessels. Am J Physiol Heart Circ Physiol 303(7):H825–H834
David S, Ghosh CC, Mukherjee A, Parikh SM (2011) Angiopoietin-1 requires IQ domain GTPase-activating protein 1 to activate Rac1 and promote endothelial barrier defense. Arterioscler Thromb Vasc Biol 31:2643–2652
David S, Kumpers P, van Slyke P, Parikh SM (2013) Mending leaky blood vessels: the angiopoietin-Tie2 pathway in sepsis. J Pharmacol Exp Ther 345(1):2–6
De Backer D, Creteur J, Dubois MJ, Sakr Y, Koch M, Verdant C, Vincent JL (2006) The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med 34:403–408
Dejana E, Orsenigo F (2013) Endothelial adherens junctions at a glance. J Cell Sci 126:2545–2549
Dejana E, Tournier-Lasserve E, Weinstein BM (2009) The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell 16:209–221
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R (2012) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 41:580–637
Ephstein Y, Singleton PA, Chen W, Wang L, Salgia R, Kanteti P, Dudek SM, Garcia JG, Jacobson JR (2013) Critical role of S1PR1 and integrin beta4 in HGF/c-Met-mediated increases in vascular integrity. J Biol Chem 288:2191–2200
Feinstein WP, Zhu B, Leavesley SJ, Sayner SL, Rich TC (2012) Assessment of cellular mechanisms contributing to cAMP compartmentalization in pulmonary microvascular endothelial cells. Am J Physiol Cell Physiol 302:C839–C852
Fischmeister R (2006) Is cAMP good or bad? Depends on where it’s made. Circ Res 98:582–584
Fiusa MM, Costa-Lima C, de Souza GR, Vigorito AC, Aranha FJ, Lorand-Metze I, Annichino-Bizzacchi JM, De Souza CA, De Paula EV (2013) A high angiopoietin-2/angiopoietin-1 ratio is associated with a high risk of septic shock in patients with febrile neutropenia. Crit Care 17(4):R169
Fu P, Birukov KG (2009) Oxidized phospholipids in control of inflammation and endothelial barrier. Transl Res 153:166–176
Fukuhara S, Sakurai A, Sano H, Yamagishi A, Somekawa S, Takakura N, Saito Y, Kangawa K, Mochizuki N (2005) Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway. Mol Cell Biol 25(1):136–146
Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, Bamberg JR, English D (2001) Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J Clin Invest 108:689–701
Glading A, Han J, Stockton RA, Ginsberg MH (2007) KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J Cell Biol 179:247–254
Goldenberg NM, Steinberg BE, Slutsky AS, Lee WL (2011) Broken barriers: a new take on sepsis pathogenesis. Sci Transl Med 3:88ps25
Hanel P, Andreani P, Graler MH (2007) Erythrocytes store and release sphingosine 1-phosphate in blood. FASEB J 21:1202–1209
He P, Zeng M, Curry FE (2000) Dominant role of cAMP in regulation of microvessel permeability. Am J Physiol Heart Circ Physiol 278:H1124–H1133
Houslay MD, Baillie GS, Maurice DH (2007) cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 100:950–966
Kim SH, Cho YR, Kim HJ, Oh JS, Ahn EK, Ko HJ, Hwang BJ, Lee SJ, Cho Y, Kim YK, Stetler-Stevenson WG, Seo DW (2012) Antagonism of VEGF-A-induced increase in vascular permeability by an integrin alpha3beta1-Shp-1-cAMP/PKA pathway. Blood 120:4892–4902
Kobayashi K, Tsubosaka Y, Hori M, Narumiya S, Ozaki H, Murata T (2013) Prostaglandin D2-DP signaling promotes endothelial barrier function via the cAMP/PKA/Tiam1/Rac1 pathway. Arterioscler Thromb Vasc Biol 33:565–571
Komarova Y, Malik AB (2010) Regulation of endothelial permeability via paracellular and transcellular transport pathways. Annu Rev Physiol 72:463–493
Kooistra MRH, Corada M, Dejana E, Bos JL (2005) Epac1 regulates integrity of endothelial cell junctions through VE-cadherin. FEBS Lett 579:4966–4972
Kumaraswamy SB, Linder A, Akesson P, Dahlback B (2012) Decreased plasma concentrations of apolipoprotein M in sepsis and systemic inflammatory response syndromes. Crit Care 16(2):R60
Kumpers P, Lukasz A, David S, Horn R, Hafer C, Faulhaber-Walter R, Fliser D, Haller H, Kielstein JT (2008) Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients. Crit Care 12(6):R147
Kumpers P, Hafer C, David S, Hecker H, Lukasz A, Fliser D, Haller H, Kielstein JT, Faulhaber-Walter R (2010) Angiopoietin-2 in patients requiring renal replacement therapy in the ICU: relation to acute kidney injury, multiple organ dysfunction syndrome and outcome. Intensive Care Med 36:462–470
Kumpers P, Gueler F, David S, Slyke PV, Dumont DJ, Park JK, Bockmeyer CL, Parikh SM, Pavenstadt H, Haller H, Shushakova N (2011) The synthetic tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis. Crit Care 15(5):R261
Lampugnani MG, Zanetti A, Breviario F, Balconi G, Orsenigo F, Corada M, Spagnuolo R, Betson M, Braga V, Dejana E (2002) VE-cadherin regulates endothelial actin activating Rac and increasing membrane association of Tiam. Mol Biol Cell 13:1175–1189
Lampugnani MG, Orsenigo F, Rudini N, Maddaluno L, Boulday G, Chapon F, Dejana E (2010) CCM1 regulates vascular-lumen organization by inducing endothelial polarity. J Cell Sci 123:1073–1080
Lee WL, Slutsky AS (2010) Sepsis and endothelial permeability. N Engl J Med 363(7):689–691
Lehtonen LA, Antila S, Pentikainen PJ (2004) Pharmacokinetics and pharmacodynamics of intravenous inotropic agents. Clin Pharmacokinet 43:187–203
Lin YC, Adamson RH, Clark JF, Reed RK, Curry FR (2012) Phosphodiesterase 4 inhibition attenuates plasma volume loss and transvascular exchange in volume-expanded mice. J Physiol 590:309–322
Liu F, Schaphorst KL, Verin AD, Jacobs K, Birukova A, Day RM, Bogatcheva N, Bottaro DP, Garcia JGN (2002) Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: potential role of glycogen synthase kinase-3-beta. FASEB J 16(9):950–962
Lugnier C, Schini VB (1990) Characterization of cyclic nucleotide phosphodiesterases from cultured bovine aortic endothelial cells. Biochem Pharmacol 39:75–84
Maharjan S, Kim K, Agrawal V, Choi HJ, Kim NJ, Kim YM, Suh YG, Kwon YG (2013) Sac-1004, a novel vascular leakage blocker, enhances endothelial barrier through the cAMP/Rac/cortactin pathway. Biochem Biophys Res Commun 435:420–427
Mammoto T, Parikh SM, Mammoto A, Gallagher D, Chan B, Mostoslavsky G, Ingber DE, Sukhatme VP (2007) Angiopoietin-1 requires p190 RhoGAP to protect against vascular leakage in vivo. J Biol Chem 282:23910–23918
McVerry BJ, Garcia JG (2005) In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights. Cell Signal 17:131–139
Mehta D, Malik AB (2006) Signaling mechanisms regulating endothelial permeability. Physiol Rev 86:279–367
Michel CC, Curry FE (1999) Microvascular permeability. Physiol Rev 79(3):703–761
Moss A (2013) The angiopoietin:Tie 2 interaction: a potential target for future therapies in human vascular disease. Cytokine Growth Factor Rev. doi:10.1016/j.cytogfr.2013.05.009
Netherton SJ, Maurice DH (2005) Vascular endothelial cell cyclic nucleotide phosphodiesterases and regulated cell migration: implications in angiogenesis. Mol Pharmacol 67(1):263–272
Ngok SP, Geyer R, Kourtidis A, Mitin N, Feathers R, Der C, Anastasiadis PZ (2013) TEM4 is a junctional Rho GEF required for cell-cell adhesion, monolayer integrity and barrier function. J Cell Sci 126:3271–3277
Nonas S, Birukova AA, Fu P, Xing J, Chatchavalvanich S, Bochkov VN, Leitinger N, Garcia JG, Birukov KG (2008) Oxidized phospholipids reduce ventilator-induced vascular leak and inflammation in vivo. Crit Care 12(1):R27
Pannekoek WJ, van Dijk JJ, Chan OY, Huveneers S, Linnemann JR, Spanjaard E, Brouwer PM, van der Meer AJ, Zwartkruis FJ, Rehmann H, de Rooij J, Bos JL (2011) Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction control. Cell Signal 23:2056–2064
Parnell E, Smith BO, Palmer TM, Terrin A, Zaccolo M, Yarwood SJ (2012) Regulation of the inflammatory response of vascular endothelial cells by EPAC1. Br J Pharmacol 166:434–446
Pyne S, Pyne N (2000) Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. Pharmacol Ther 88:115–131
Qiao J, Huang F, Lum H (2003) PKA inhibits RhoA activation: a protection mechanism against endothelial barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 284:L972–L980
Rigor RR, Shen Q, Pivetti CD, Wu MH, Yuan SY (2012) Myosin light chain kinase signaling in endothelial barrier dysfunction. Med Res Rev 33:911–933
Risoe PK, Wang Y, Stuestol JF, Aasen AO, Wang JE, Dahle MK (2007) Lipopolysaccharide attenuates mRNA levels of several adenylyl cyclase isoforms in vivo. Biochim Biophys Acta 1772:32–39
Sayner SL, Alexeyev M, Dessauer CW, Stevens T (2006) Soluble adenylyl cyclase reveals the significance of cAMP compartmentation on pulmonary microvascular endothelial cell barrier. Circ Res 98:675–681
Schick MA, Wunder C, Wollborn J, Roewer N, Waschke J, Germer CT, Schlegel N (2012) Phosphodiesterase-4 inhibition as a therapeutic approach to treat capillary leakage in systemic inflammation. J Physiol 590:2693–2708
Schlegel N, Waschke J (2009a) Impaired cAMP and Rac 1 signaling contribute to TNF-alpha-induced endothelial barrier breakdown in microvascular endothelium. Microcirculation 16(6):521–533
Schlegel N, Waschke J (2009b) Impaired integrin-mediated adhesion contributes to reduced barrier properties in VASP-deficient microvascular endothelium. J Cell Physiol 220:357–366
Schlegel N, Waschke J (2009c) VASP is involved in cAMP-mediated Rac 1 activation in microvascular endothelial cells. Am J Physiol Cell Physiol 296(3):C453–C462
Schlegel N, Waschke J (2010) Vasodilator-stimulated phosphoprotein: crucial for activation of Rac1 in endothelial barrier maintenance. Cardiovasc Res 87(1):1–3
Schlegel N, Burger S, Golenhofen N, Walter U, Drenckhahn D, Waschke J (2008) The role of VASP in regulation of cAMP- and Rac 1-mediated endothelial barrier stabilization. Am J Physiol Cell Physiol 294:C178–C188
Schlegel N, Baumer Y, Drenckhahn D, Waschke J (2009) Lipopolysaccharide-induced endothelial barrier breakdown is cAMP dependent in vivo and in vitro*. Crit Care Med 37(5):1735–1743
Schlegel N, Leweke R, Meir M, Germer CT, Waschke J (2012) Role of NF-kappaB activation in LPS-induced endothelial barrier breakdown. Histochem Cell Biol 138:627–641
Schnoor M, Lai FP, Zarbock A, Klaver R, Polaschegg C, Schulte D, Weich HA, Oelkers JM, Rottner K, Vestweber D (2011) Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo. J Exp Med 208:1721–1735
Secchi A, Ortanderl JM, Schmidt W, Walther A, Gebhard MM, Martin E, Schmidt H (2001) Effects of dobutamine and dopexamine on hepatic micro- and macrocirculation during experimental endotoxemia: an intravital microscopic study in the rat. Crit Care Med 29:597–600
Sehrawat S, Ernandez T, Cullere X, Takahashi M, Ono Y, Komarova Y, Mayadas TN (2011) AKAP9 regulation of microtubule dynamics promotes Epac1-induced endothelial barrier properties. Blood 117(2):708–718
Shen Q, Rigor RR, Pivetti CD, Wu MH, Yuan SY (2010) Myosin light chain kinase in microvascular endothelial barrier function. Cardiovasc Res 87:272–280
Singleton PA, Salgia R, Moreno-Vinasco L, Moitra J, Sammani S, Mirzapoiazova T, Garcia JGN (2007) CD44 regulates hepatocyte growth factor-mediated vascular integrity: ROLE OF c-Met, Tiam1/Rac1, DYNAMIN 2, and CORTACTIN. J Biol Chem 282(42):30643–30657
Singleton PA, Chatchavalvanich S, Fu P, Xing J, Birukova AA, Fortune JA, Klibanov AM, Garcia JG, Birukov KG (2009) Akt-mediated transactivation of the S1P1 receptor in caveolin-enriched microdomains regulates endothelial barrier enhancement by oxidized phospholipids. Circ Res 104:978–986
Spindler V, Waschke J (2011) Beta-adrenergic stimulation contributes to maintenance of endothelial barrier functions under baseline conditions. Microcirculation 18:118–127
Spindler V, Schlegel N, Waschke J (2010) Role of GTPases in control of microvascular permeability. Cardiovasc Res 87(2):243–253
Spindler V, Peter D, Harms GS, Asan E, Waschke J (2011) Ultrastructural analysis reveals cAMP-dependent enhancement of microvascular endothelial barrier functions via Rac1-mediated reorganization of intercellular junctions. Am J Pathol 178:2424–2436
Starosta V, Wu T, Zimman A, Pham D, Tian X, Oskolkova O, Bochkov V, Berliner JA, Birukova AA, Birukov KG (2012) Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine. Am J Respir Cell Mol Biol 46:331–341
Stephens CT, Uwaydah N, Kramer GC, Prough DS, Salter M, Kinsky MP (2011) Vascular and extravascular volume expansion of dobutamine and norepinephrine in normovolemic sheep. Shock 36:303–311
Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD (2000) Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 6:460–463
Tian X, Tian Y, Sarich N, Wu T, Birukova AA (2012) Novel role of stathmin in microtubule-dependent control of endothelial permeability. FASEB J 26:3862–3874
Wang D, Luo P, Wang Y, Li W, Wang C, Sun D, Zhang R, Su T, Ma X, Zeng C, Wang H, Ren J, Cao F (2013) Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. Diabetes 62:1697–1708
Ware LB, Matthay MA (2002) Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 282(5):L924–L940
Waschke J, Baumgartner W, Adamson RH, Zeng M, Aktories K, Barth H, Wilde C, Curry FE, Drenckhahn D (2004a) Requirement of Rac activity for maintenance of capillary endothelial barrier properties. Am J Physiol Heart Circ Physiol 286:H394–H401
Waschke J, Drenckhahn D, Adamson RH, Barth H, Curry FE (2004b) cAMP protects endothelial barrier functions by preventing Rac-1 inhibition. Am J Physiol Heart Circ Physiol 287:H2427–H2433
Waschke J, Drenckhahn D, Adamson RH, Curry FE (2004c) Role of adhesion and contraction in Rac 1-regulated endothelial barrier function in vivo and in vitro. Am J Physiol Heart Circ Physiol 287:H704–H711
Waschke J, Curry FE, Adamson RH, Drenckhahn D (2005) Regulation of actin dynamics is critical for endothelial barrier functions. Am J Physiol Heart Circ Physiol 288:H1296–H1305
Waschke J, Burger S, Curry FR, Drenckhahn D, Adamson RH (2006) Activation of Rac-1 and Cdc42 stabilizes the microvascular endothelial barrier. Histochem Cell Biol 125:397–406
Zebda N, Tian Y, Tian X, Gawlak G, Higginbotham K, Reynolds AB, Birukova AA, Birukov KG (2013) Interaction of p190RhoGAP with C-terminal domain of p120-catenin modulates endothelial cytoskeleton and permeability. J Biol Chem 288(25):18290–18299
Ziegler T, Horstkotte J, Schwab C, Pfetsch V, Weinmann K, Dietzel S, Rohwedder I, Hinkel R, Gross L, Lee S, Hu J, Soehnlein O, Franz WM, Sperandio M, Pohl U, Thomas M, Weber C, Augustin HG, Fassler R, Deutsch U, Kupatt C (2013) Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis. J Clin Invest. doi:10.1172/JCI66549
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Schlegel, N., Waschke, J. cAMP with other signaling cues converges on Rac1 to stabilize the endothelial barrier— a signaling pathway compromised in inflammation. Cell Tissue Res 355, 587–596 (2014). https://doi.org/10.1007/s00441-013-1755-y
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DOI: https://doi.org/10.1007/s00441-013-1755-y