Keeping blood vessels tight – how the Tie-2 signalling pathway prevents leaks during immune cell extravasation
MTZ®-MPI-Award 2019 to Dr. Laura Braun
The MTZ®foundation will be honouring Dr. Laura Braun on 20 November 2019. She completed an important doctoral thesis on the barrier function of blood vessels as part of the deparmtent of Professor Dr. Dietmar Vestweber at the Max Planck Institute (MPI) for Molecular Biomedicine. Since 2009, the MTZ®foundation has honoured young scientists at the MPI for Molecular Biomedicine every year with the MTZ®-MPI-Award, which includes a prize in the amount of EUR 2,500. In this way, the benefactors, the married couple Monika and Thomas Zimmermann, want to help young scientists on their route into research.
Whenever foreign substances or tissue injuries stimulate our immune system, the body rapidly responds with an inflammation. This makes it possible to sufficiently supply the affected tissue with nutrients and allow immune cells to be released in order to fight the infection.
These processes are controlled via the cells of the blood vessel wall, the endothelial cells. The permeability of the endothelial cell layer is increased around the centre of inflammation, which allows plasma proteins and immune cells to enter the tissue. While this local increase in endothelial permeability is absolutely essential to fight an infection locally, ongoing hyperpermeability can cause severe and irreparable damage, for instance after a heart attack or a stroke, during acute respiratory distress syndrome, diabetes or sepsis. Understanding the signalling pathways that act in endothelial cells to control vessel permeability thus forms the basis for the development of treatments for these disorders.
In her doctoral thesis, Laura Braun investigated such a signalling pathway which is controlled by the endothelial kinase Tie-2. Tie-2 is a receptor tyrosine kinase, meaning a receptor bound to the cell membrane whose intracellular domain carries an enzyme group, the tyrosine kinase. Activation of Tie-2 induces a re-organization of the actin cytoskeleton, which is basically the scaffolding of the cell: destabilizing structures called stress fibres are dissolved and stabilizing structures called cortical actin form.
The protein FGD5, which was characterized by Laura Braun in her doctoral thesis, is a crucial, previously unknown parameter in the signalling path stimulated by Tie-2. “FGD5 is an important actin regulator,” Laura Braun says. “Its activation is a prerequisite for stress fibres to be broken down and cortical actin to form and thus for the stabilization of the endothelial barrier.”
Actin regulation by Tie-2 and FGD5 plays an important role in the context of the inflammatory response: it prevents passive leakage through the vessel wall during immune cell extravasation. “It is astounding that a complete immune cell can force its way through the endothelial cell layer without passive loss of fluid. I have been able to show that Tie-2 and FGD5 are needed in order to prevent this passive leakage by stimulating the formation of a cortical actin ring around the emigrating immune cells,” Laura Braun says. This ring restricts the opening created for the cell and contacts firmly while it crosses the endothelial cell layer. This prevents leaks and maintains the barrier.
The stabilizing effect of Tie-2 has vast clinical potential. Today, Tie-2 activators are already tested in clinical studies to treat diseases characterized by blood vessel instability. A better understanding of the processes controlled by Tie-2 could smooth the path for further treatments.
About Laura Braun
Laura Braun (31) studied Biosciences and Molecular Biomedicine at the University of Münster. During her Master’s degree, she completed research at the Karolinska Institute in Stockholm, Sweden, before starting her doctoral thesis in the working group of Dietmar Vestweber at the Max Planck Institute for Molecular Biomedicine in 2014. She successfully defended her thesis in June 2018. Her data resulted in two publications: One has already been published in EMBO Reports, the other is currently being reviewed by the reputable specialist journal Blood.