Lehrstuhl I Anatomie
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Inhaltsbereich

Endothelial barrier dysfunction and inflammation

Members:

Mariya Radeva and Jens Waschke (group leaders)
Daniela Kugelmann (postdoctoral fellow)
Alexander Garcia Ponce (postdoctoral fellow)
Lukas Rotkopf (MD student)
Katharina Schuster (MD student)
Marlene Delivuk (technician)

 

Under allergic and inflammatory conditions, the functional integrity of the endothelium lining the inner surface of the blood vessels is reduced primarily by intercellular gap formation. This effect is associated with reduced endothelial barrier function and increased paracellular permeability. Our previous studies demonstrated that cyclic adenosine monophosphate (cAMP)-mediated activation of the small GTPase Rac1 is an essential signaling step required for stabilization of endothelial barrier function (Figure 1). In this respect, it was shown that Rac1 can be activated by both exchange protein directly activated by cAMP (Epac1)/ Ras-related protein 1 (Rap1) and protein kinase A (PKA)-dependent signaling pathways. Furthermore, it is a well-known fact that tight regulation of PKA function can be achieved by discrete compartmentalization of the enzyme via physical interaction with A-kinase anchoring proteins (AKAPs). Apparently, this signalling pathway is impaired in inflammation and sepsis as cAMP levels decrease and Rac1 is inactivated contributing to endothelial barrier breakdown (Figure 2).

 

endothel-fig1

Figure 1

Therefore, one of the project aims is to determine the functional relevance of AKAP molecules for maintenance of endothelial barrier integrity and cytoskeleton reorganization. So far we found AKAP220 and AKAP12 to be new candidates.

Furthermore, since a growing number of actin-binding proteins such as vasodilator-stimulated phosphoprotein (VASP), cortactin and adducin may play a significant role in cytoskeletal and junctional remodeling, we study the role of actin binding proteins in the regulation of the endothelial barrier.

In our studies, in vivo assessment of the microvascular permeability in single postcapillary venules from rat mesenteries as well as in vitro transendothelial resistance (TER) measurements in cell monolayers will be combined with structural, pharmacological and biochemical investigations. AFM and laser tweezers will be used to study effects on VE-cadherin transinteraction.

 

endothel-fig2

Figure 2

 

Publications:
Waschke J, Baumgartner W, Adamson RH, Zeng M, Aktories K, Barth H, Wilde C, Curry FE, Drenckhahn D (2004) Requirement of Rac activity for maintenance of capillary endothelial barrier properties. Am. J. Physiol. Heart Circ. Physiol. 286: H394-401

Waschke J, Drenckhahn D, Adamson RH, Curry FE (2004) Role of adhesion and contraction in Rac 1-regulated endothelial barrier function in vivo and in vitro. Am. J. Physiol. Heart Circ. Physiol. 287: H704-711

Waschke J, Drenckhahn D, Adamson RH, Barth H, Curry FE (2004) cAMP protects endothelial barrier functions by preventing Rac-1 inhibition. Am. J. Physiol. Heart Circ. Physiol. 287: H2427-433

Waschke J, Adamson RH, Curry FE, Drenckhahn D (2005) Regulation of actin dynamics is critical for endothelial barrier functions. Am. J. Physiol. Heart Circ. Physiol. 288: H1296-305

Waschke J, Burger S, Curry FE, Drenckhahn D, Adamson RH (2006) Activation of Rac-1 and Cdc42 stabilizes the microvascular endothelial barrier. Histochem. Cell Biol. 125(4): 397-406

Waschke J, Golenhofen N, Kurzchalia, TV, Drenckhahn D (2006) Protein kinase C-mediated endothelial barrier regulation is caveolin 1-dependent. Histochem. Cell Biol.126 (1): 17-26

Förster C, Waschke J, Burek M, Leers J, Drenckhahn D (2006) Glucocorticoid effects on microvascular endothelial barrier permeability are brain specific. J. Physiol. 573(Pt2): 413-425

Chtcheglova L, Waschke J, Wildling L, Drenckhahn D, Hinterdorfer P (2007) Nano-Scale dynamic recognition imaging on vascular endothelial cells. Biophys. J., 15; 93: L11-13

Müller-Marschhausen K, Waschke J, Drenckhahn, D (2008) Physiological hydrostatic pressure protects endothelial monolayer integrity in vitro. Am. J. Physiol. Cell Physiol., 294(1):C324-332

Baumer Y, Burger S, Curry FE, Golenhofen N, Drenckhahn D, Waschke J (2008) Different role of Rho GTPases in endothelial barrier regulation dependent on endothelial cell origin. Histochem. Cell Biol., 129(2): 179-191

Schlegel N, Burger S, Golenhofen N, Walter U, Drenckhahn D, Waschke J (2008) The role of VASP in the regulation of cAMP- and Rac 1-mediated endothelial barrier stabilization. Am. J. Physiol. Cell Physiol., 294(1): c178-188

Baumer Y, Drenckhahn D, Waschke J (2008) cAMP induced Rac 1-mediated cytoskeletal reorganization in microvascular endothelium. Histochem. Cell Biol., 129(6): 765-778

Samarin J, Rehm M, Krueger B, Waschke J, Goppelt-Struebe M (2009) Up-regulation of connective tissue growth factor in endothelial cells by the microtubule-destabilizing agent combretastatin A-4. Mol. Cancer Res, 7(2): 180-188

Schlegel N, Waschke J (2009) VASP is involved in cAMP-mediated Rac 1 activation in microvascular endothelial cells. AJP Cell Physiology, 296(3): C453-462

Schlegel N, Baumer Y, Drenckhahn D, Waschke J (2009) LPS-induced endothelial barrier breakdown is cAMP-dependent in vivo and in vitro. Crit. Care Med., 37(5): 1735-43

Schlegel N, Waschke J (2009) Impaired integrin-mediated adhesion contributes to reduced barrier properties in VASP-deficient microvascular endothelium. J. Cell. Physiol, 220:357-366

Baumer Y, Spindler V, Werthmann R, Buenemann M, Waschke J (2009) Role of Rac 1 and cAMP in endothelial barrier stabilization and thrombin-induced barrier breakdown, J. Cell Physiol., 220: 716-726

Schlegel N, Waschke J (2009) Impaired cAMP and Rac 1 signalling contribute to TNF-α-induced endothelial barrier breakdown in microvascular endothelium. Microcirculation, 16: 521-533

Schick MA, Isbary TJ, Schlegel N, Brugger J, Waschke J, Muellenbach R, Roewer N, Wunder C (2010) The impact of crystalloid infusion on the kidney in rodent sepsis. Intensive Care Med., 36(3). 541-548

Benz PM, Blume C, Seifert S, Wilhelm S, Waschke J, Schuh K, Gertler F, Münzel T, Renné T (2010) Differential VASP phosphorylation controls remodeling of the actin cytoskeleton. J. Cell Sci., 122:3954-3965

Chtcheglova L, Wildling L, Waschke J, Drenckhahn D, Hinterdorfer P (2010) AFM functional imaging on vascular endothelial cells.. J.Mol.Recognit., 23(6): 598-596

Spindler V, Waschke J (2011) Beta-adrenergic stimulation contributes to maintenance of endothelial functions under baseline conditions. Microcirculation, 18(2): 118-127

Chen W, Gaßner B, Börner S, Nikolaev VO, Schlegel N, Waschke J, Steinbronn N, Strasser R, Kuhn M (2012) Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway. Cardiovasc Res., 93(1): 141-151

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(5):2424-2436

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(Pt 11):2693-2708

Schlegel N, Leweke R, Meir M., Germer CT, Waschke J (2012) Role of NF-κB activation in LPS-induced endothelial barrier breakdown. Histochem. Cell Biol., 138(4):627-641

Radeva MY, Kugelmann D, Spindler V, Waschke J (2014) PKA compartmentalization via AKAP220 and AKAP12 contributes to endothelial barrier regulation. PLoS One.; 9(9)

Adamson RH, Clark JF, Radeva M, Kheirolomoom A, Ferrara KW, Curry FE. (2014) Albumin modulates S1P delivery from red blood cells in perfused microvessels: mechanism of the protein effect. Am J Physiol Heart Circ Physiol. 2014 Apr 1;306(7):H1011-7. doi: 10.1152/ajpheart.00829.2013. Epub 2014 Feb 14. Erratum in: Am J Physiol Heart Circ Physiol. 2014 Jul 1;307(1):H120

Flemming S, Burkard N, Renschler M, Vielmuth F, Meir M, Schick MA, Wunder C, Germer CT, Spindler V, Waschke J, Schlegel N (2015) Soluble VE-cadherin is involved in endothelial barrier breakdown in systemic inflammation and sepsis. Cardiovasc Res., 107(1):32-44

Kugelmann D, Waschke J, Radeva MY (2015) Adducin is involved in endothelial barrier stabilization. PLoS One;10(5)

Kugelmann D, Rotkopf LT, Radeva MY, Garcia-Ponce A, Walter E, Waschke J. (2018) Histamine causes endothelial barrier disruption via Ca2+-mediated RhoA activation and tension at adherens junctions. Sci Rep. 2018 Sep 5;8(1):13229. doi: 10.1038/s41598-018-31408-3

 

 

Reviews:


Spindler V, Schlegel N, Waschke J (2010) Role of GTPases in control of microvascular permeability. Cardiovasc.Res., 87(2):243-253

Schlegel N, Waschke J (2010) Vasodilator-stimulated phosphoprotein (VASP): Crucial for activation of Rac1 in endothelial barrier maintenance. Cardiovasc.Res., 87(1):1-3

Schlegel N, Waschke J (2014) cAMP with other signaling cues converges on Rac1 to stabilize the endothelial barrier- a signaling pathway compromised in inflammation. Cell Tissue Res. 355(3):587-96

Radeva M, Waschke J (2017) Mind the gap- mechanisms regulating the endothelial barrier. Acta Physiol., 222(1)