Regulation of vascular permeability and leukocyte extravasation in inflammation: mechanisms and heterogeneity in different organs

Principal investigator: Dietmar Vestweber
Project number: CRC 1450 B03
Project term: 01/2021–12/2024

Graphical abstract
© CRC inSight

It has recently emerged that the molecular mechanisms and requirements which control the integrity of the endothelial barrier vary significantly between different organs. This project will analyse how VE-cadherin regulates vascular permeability of the endothelium in different tissues (1, 2).

We will focus on the role of posttranslational modifications of certain residues for which we have or will generate and analyse point mutated knock-in mice (3). In a second part, it will be investigated whether the preferential use of the leukocyte diapedesis route through endothelium (trans-junctional versus transcellular) varies in different organs and which molecular mechanisms influence this choice (4). This will be analysed with the help of knock-in mice where due to directly fusing VE-cadherin with ɑ-catenin the trans-junctional pathway is blocked (5, 6).


Principal investigator

Project members


The names of the principal investigators in our network have been bolded. Publications released prior to 2021, when funding for our network commenced, represent previous project-related work.


Faust A, Baumer N, Schlutermann A, Becht M, Greune L, Geyer C, Ruter C, Margeta R, Wittmann L, Dersch P, Lenz G, Berdel WE, Baumer S. Tumor-Cell-Specific Targeting of Ibrutinib: Introducing Electrostatic Antibody-Inhibitor Conjugates (AiCs). Angew Chem Int Ed Engl 2022;61: e202109769. Abstract


Duong CN, Nottebaum AF, Butz S, Volkery S, Zeuschner D, Stehling M, Vestweber D. Interference With ESAM (Endothelial Cell-Selective Adhesion Molecule) Plus Vascular Endothelial-Cadherin Causes Immediate Lethality and Lung-Specific Blood Coagulation. Arterioscler Thromb Vasc Biol 2020;40: 378-393. Abstract
Owen-Woods C, Joulia R, Barkaway A, Rolas L, Ma B, Nottebaum AF, Arkill KP, Stein M, Girbl T, Golding M, Bates DO, Vestweber D, Voisin M-B, Nourshargh S. Local microvascular leakage promotes trafficking of activated neutrophils to remote organs. J Clin Invest 2020;130: 2301-2318. Abstract
Rademakers T, Goedhart M, Hoogenboezem M, Garcia Ponce A, van Rijssel J, Samus M, Schnoor M, Butz S, Huveneers S, Vestweber D, Nolte MA, Voermans C, van Buul JD. Hematopoietic stem and progenitor cells use podosomes to transcellularly cross the bone marrow endothelium. Haematologica 2020;105: 2746-2756. Abstract


Braun LJ, Zinnhardt M, Vockel M, Drexler HC, Peters K, Vestweber D. VE-PTP inhibition stabilizes endothelial junctions by activating FGD5. EMBO Rep 2019;20: e47046. Abstract


Conway DE, Coon BG, Budatha M, Arsenovic PT, Orsenigo F, Wessel F, Zhang J, Zhuang Z, Dejana E, Vestweber D, Schwartz MA. VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Curr Biol 2017;27: 2219-2225.e5. Abstract


Barreiro O, Cibrian D, Clemente C, Alvarez D, Moreno V, Valiente I, Bernad A, Vestweber D, Arroyo AG, Martin P, von Andrian UH, Sanchez Madrid F. Pivotal role for skin transendothelial radio-resistant anti-inflammatory macrophages in tissue repair. Elife 2016;5: e15251. Abstract


Frye M, Dierkes M, Kuppers V, Vockel M, Tomm J, Zeuschner D, Rossaint J, Zarbock A, Koh GY, Peters K, Nottebaum AF, Vestweber D. Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. J Exp Med 2015;212: 2267-2287. Abstract
Vestweber D. How leukocytes cross the vascular endothelium. Nat Rev Immunol 2015;15: 692-704. Abstract


Wessel F, Winderlich M, Holm M, Frye M, Rivera-Galdos R, Vockel M, Linnepe R, Ipe U, Stadtmann A, Zarbock A, Nottebaum AF, Vestweber D. Leukocyte extravasation and vascular permeability are each controlled in vivo by different tyrosine residues of VE-cadherin. Nat Immunol 2014;15: 223-230. Abstract


Schulte D, Kuppers V, Dartsch N, Broermann A, Li H, Zarbock A, Kamenyeva O, Kiefer F, Khandoga A, Massberg S, Vestweber D. Stabilizing the VE-cadherin-catenin complex blocks leukocyte extravasation and vascular permeability. EMBO J 2011: 4157-70. Abstract