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).

Team

Principal investigator

Project members

Publications

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.

2023

Bauer N, Maisuls I, Pereira da Graca A, Reinhardt D, Erapaneedi R, Kirschnick N, Schafers M, Grashoff C, Landfester K, Vestweber D, Strassert CA, Kiefer F. Genetically encoded dual fluorophore reporters for graded oxygen-sensing in light microscopy. Biosens Bioelectron 2023;221: 114917. Abstract

2022

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
Jin Y, Ding Y, Richards M, Kaakinen M, Giese W, Baumann E, Szymborska A, Rosa A, Nordling S, Schimmel L, Akmeric EB, Pena A, Nwadozi E, Jamalpour M, Holstein K, Sainz-Jaspeado M, Bernabeu MO, Welsh M, Gordon E, Franco CA, Vestweber D, Eklund L, Gerhardt H, Claesson-Welsh L. Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis. Nat Cardiovasc Res 2022;1: 1156-1173. Abstract

2021

Duong CN, Bruckner R, Schmitt M, Nottebaum AF, Braun LJ, Meyer Zu Brickwedde M, Ipe U, Vom Bruch H, Scholer HR, Trapani G, Trappmann B, Ebrahimkutty MP, Huveneers S, de Rooij J, Ishiyama N, Ikura M, Vestweber D. Force-induced changes of alpha-catenin conformation stabilize vascular junctions independently of vinculin. J Cell Sci 2021;134Abstract
Ninchoji T, Love DT, Smith RO, Hedlund M, Vestweber D, Sessa WC, Claesson-Welsh L. eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin. Elife 2021;10Abstract

2020

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

2019

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

2017

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