A major research topic of the group aims at understanding the cell biological principles that ensure intactness of blood vessels and that control leukocyte extravasation and vascular permeability in various pathological settings (Vestweber, 2015). Endothelial cells form the inner layer of the blood vessel wall and control when and where cellular and soluble components of the blood enter tissue. The junctions between endothelial cells are the central exit sites, which are opened either by inflammatory stimuli or directly by leukocytes that become captured to the luminal endothelial surface. We have shown recently that phosphorylation of certain tyrosine residues of VE-cadherin control this process in vivo(Wessel et al., 2014). Interestingly, different tyrosine residues were addressed by the induction of vascular permeability and the exit of leukocytes. This highlights the central role of VE-cadherin for each process in vivo and reveals that the stability of endothelial junctions and the function of VE-cadherin are differently affected by these two different patho-physiological processes.
Despite the central role of VE-cadherin for the integrity of the blood vessel wall, we found recently that induced gene-inactivation of VE-cadherin disrupted endothelial junctions only in some (heart, lung) but not in all organs (skin, brain)(Frye et al., 2015). In addition, this study revealed that the endothelial specific receptor type tyrosine phosphatase VE-PTP regulates endothelial junctions in vivo by regulating VE-cadherin adhesive function as well as by balancing the tyrosine kinase activity of Tie-2. The strong supportive effect of Tie-2 on junction stability makes the VE-PTP/Tie-2 complex a valuable target for therapeutic treatment of vascular leakiness(Shen et al., 2014).
In additional projects, we have analyzed how endothelial junctions control blood vessel development (Bentley et al., 2014), how platelets ensure blood vessel integrity during inflammation (Hillgruber et al., 2015) and how the activation of leukocytes and their integrins is controlled in the context of leukocyte recruitment into tissues (Artz et al., 2016) (Goswami et al., 2017).
- Artz, A., Butz, S., and Vestweber, D. (2016). GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-βRII heterodimer. Blood 128, 529-541.
- Bentley, K., Franco, C.A., Philippides, A., Blanco, R., Dierkes, M., Gebala, V., Stanchi, F., Jones, M., Aspalter, I.M., Cagna, G., et al. (2014). The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis. Nat Cell Biol 16, 309-321.
- Frye, M., Dierkes, M., Küppers, V., Vockel, M., Tomm, J., Zeuschner, D., Rossaint, J., Zarbock, A., Koh, G.Y., Peters, K., et al. (2015). Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. J Exp Med 212, 2267-2287.
- Goswami, D., März, S., Li, Y.T., Artz, A., Schäfer, K., Seelige, R., Pacheco-Blanco, M., Jing, D., Bixel, M.G., Araki, M., et al. (2017). Endothelial CD99 supports arrest of mouse neutrophils in venules and binds to neutrophil PILRs. Blood 129, 1811-1822.
- Hillgruber, C., Pöppelmann, B., Weishaupt, C., Steingräber, A.K., Wesele, F., Berdel, W.E., Gessner, J.E., Ho-Tin-Noe, B., Vestweber, D., and Goerge, T. (2015). Blocking neutrophil diapedesis prevents hemorrhage during thrombocytopenia. J Exp Med 212, 1255-1266.
- Shen, J., Frye, M., Lee, B.L., Reinardy, J.L., McClung, J.M., Ding, K., Kojima, M., Xia, H., Seidel, C., Lima e Silva, R., et al. (2014). Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest 124, 4564-4576.
- Vestweber, D. (2015). How leukocytes cross the vascular endothelium. Nat Rev Immunol 15, 692-704.
- Wessel, F., Winderlich, M., Holm, M., Frye, M., Rivera-Galdos, R., Vockel, M., Linnepe, R., Ipe, U., Stadtmann, A., Zarbock, A., et al. (2014). Leukocyte extravasation and vascular permeability are each controlled in vivo by a different tyrosine residue of VE-cadherin. Nat Immunol 15, 223-230.