Thesis Lilian Schimmel
On 15 June 2018 Lilian Schimmel defended her thesis 'Filling the gaps; The endothelium in regulating vascular leakage and leukocyte extravasation' at the University of Amsterdam.
Promotor: Prof PL Hordijk PhD
Copromotores: JD van Buul PhD and V de Waard PhD
Venue: Universiteit van Amsterdam, Agnietenkapel
Summary

In this thesis, we demonstrate the active role of the endothelium during the process of leukocyte transendothelial migration (TEM). In particular we focused on the role of the actin cytoskeleton, its regulation by the Rho family of small GTPases, and their spatiotemporal activation and deactivation by guanine nucleotide exchange factors (GEFs) and GTPase activing proteins (GAPs) respectively. Although many efforts have been made, we still know relatively little on the true contribution of Rho GTPases in the process of leukocyte TEM. The work presented in this thesis contributes to the elucidation and regulation of some of the most well-studied family members such as RhoA and Rac1, but also shows some more insight in the less investigated family members like RhoB, RhoC and Cdc42. We showed that leukocyte TEM and vascular permeability are two uncoupled events, and endothelial cells play a major role in actively limiting vascular permeability while leukocytes pass. Moreover, we showed how changes in the microenvironment such as increased tissue stiffness affects the endothelial cells and their behavior regarding the regulation of leukocyte TEM. However, future studies into the upstream activation and regulation of the involved GEFs is essential to completely understand the exact signaling pathways and mechanisms. Once the signaling pathways are elucidated, we can use this knowledge to interfere with these processes to develop potential therapies to target vascular diseases in which leukocyte extravasation is the underlying cause.
Chapters
Chapter 1
General introduction
Chapter 2
Leukocyte transendothelial migration: A local affair abstract
Chapter 3
F-actin rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signaling abstract
Chapter 4
Endothelial RhoB and RhoC are dispensable for leukocyte diapedesis and for maintaining vascular integrity during diapedesis abstract
Chapter 5
The Rho-GEFs FGD5 and Tuba differentially regulate the small GTPase Cdc42 to control leukocyte extravasation and vascular permeability
Chapter 6
Stiffness-induced endothelial DLC-1 expression forces leukocyte spreading through stabilization of the ICAM-1 adhesome
Chapter 7
Rac1 activation by the endothelial GEF Tiam1 marks sites for leukocyte diapedesis through guiding junctional membrane ruffles
Chapter 8
Summary and concluding remarks
Download
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