| 1. |
- Daubel, Nina
(author)
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Lymphatic Vascular Morphogenesis : From Progenitors to Functional Vessels
- 2022
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Doctoral thesis (other academic/artistic)abstract
- The lymphatic vasculature is an important part of the circulatory system and crucial for normal functioning and maintenance of tissues. Yet, our understanding of the processes underlying lymphatic development and homeostasis are surprisingly limited. Recent studies have uncovered a heterogeneous origin of lymphatic endothelium within different organs as well as different mechanisms of vessel formation. The mesentery is a fold of peritoneum that attaches the intestines to the abdominal wall and harbours nerves, blood and lymphatic vessels which supply the intestines. Here, the lymphatic vasculature forms through a process termed lymphvasculogenesis, during which non-venous derived lymphatic endothelial cell (LEC) progenitors assemble into vessels. Parallel to this process, the mesenteric blood vasculature undergoes extensive remodelling. In paper II we show that this is accompanied by a transient extravasation of red blood cells (RBCs). Engulfment of RBCs by developing lymphatic vessels indicate a novel role of lymphatics in clearance of extravasated RBCs. In paper III we further analyse early LEC progenitors in the mesentery and show that they exhibit unique characteristics including membrane blebbing that may facilitate LEC migration during lymphvasculogenic vessel formation. The primitive lymphatic plexus further develops into mature vessels with blind ended, highly specialized segments termed lymphatic capillaries. Individual capillary LECs possess a characteristic oak leaf like shape and discontinuous button like junctions. In paper IV we propose a new model of cell shape regulation in lymphatic capillaries that is based on the interplay of the cytoskeleton and a unique organization of cell-cell junctions. We further report that acquisition of oak leaf shape precedes junctional specification, and is not a mere result of button junction formation in dermal lymphatics. CreERT2 mouse lines are used across many fields of biological research, including the here presented studies, because they allow for targeted gene deletion upon inducible genetic recombination. In paper I we report that, unexpectedly, several commonly used CreERT2 mouse lines exhibit a weak baseline Cre activity leading to induction-independent recombination. This has important implications for the interpretation of results from Cre/loxP experiments, especially when performing lineage tracing.Focusing on different aspects of lymphatic vascular biology, this thesis work reveals yet undescribed mechanisms by which LECs form new vessels, contribute to tissue integrity during vascular remodelling and maintain mature lymphatic vessel integrity through a unique interplay of cell shape and junctional organization.
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| 2. |
- Hayashi, Makoto, et al.
(author)
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VE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation
- 2013
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 4, s. 1672-
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Journal article (peer-reviewed)abstract
- Vascular endothelial growth factor (VEGF) guides the path of new vessel sprouts by inducing VEGF receptor-2 activity in the sprout tip. In the stalk cells of the sprout, VEGF receptor-2 activity is downregulated. Here, we show that VEGF receptor-2 in stalk cells is dephosphorylated by the endothelium-specific vascular endothelial-phosphotyrosine phosphatase (VE-PTP). VE-PTP acts on VEGF receptor-2 located in endothelial junctions indirectly, via the Angiopoietin-1 receptor Tie2. VE-PTP inactivation in mouse embryoid bodies leads to excess VEGF receptor-2 activity in stalk cells, increased tyrosine phosphorylation of VE-cadherin and loss of cell polarity and lumen formation. Vessels in ve-ptp(-/-) teratomas also show increased VEGF receptor-2 activity and loss of endothelial polarization. Moreover, the zebrafish VE-PTP orthologue ptp-rb is essential for polarization and lumen formation in intersomitic vessels. We conclude that the role of Tie2 in maintenance of vascular quiescence involves VE-PTP-dependent dephosphorylation of VEGF receptor-2, and that VEGF receptor-2 activity regulates VE-cadherin tyrosine phosphorylation, endothelial cell polarity and lumen formation.
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| 3. |
- Hultin, Sara, et al.
(author)
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AmotL2 links VE-cadherin to contractile actin fibres necessary for aortic lumen expansion
- 2014
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5
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Journal article (peer-reviewed)abstract
- The assembly of individual endothelial cells into multicellular tubes is a complex morphogenetic event in vascular development. Extracellular matrix cues and cell-cell junctional communication are fundamental to tube formation. Together they determine the shape of endothelial cells and the tubular structures that they ultimately form. Little is known regarding how mechanical signals are transmitted between cells to control cell shape changes during morphogenesis. Here we provide evidence that the scaffold protein amotL2 is needed for aortic vessel lumen expansion. Using gene inactivation strategies in zebrafish, mouse and endothelial cell culture systems, we show that amotL2 associates to the VE-cadherin adhesion complex where it couples adherens junctions to contractile actin fibres. Inactivation of amotL2 dissociates VE-cadherin from cytoskeletal tensile forces that affect endothelial cell shape. We propose that the VE-cadherin/amotL2 complex is responsible for transmitting mechanical force between endothelial cells for the coordination of cellular morphogenesis consistent with aortic lumen expansion and function.
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| 4. |
- Kotini, Maria Paraskevi, et al.
(author)
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Sprouting and anastomosis in the Drosophila trachea and the vertebrate vasculature : Similarities and differences in cell behaviour
- 2019
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In: Vascular pharmacology. - : Elsevier. - 1537-1891 .- 1879-3649. ; 112, s. 8-16
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Journal article (peer-reviewed)abstract
- Branching morphogenesis is a fascinating process whereby a simple network of biological tubes increases its complexity by adding new branches to existing ones, generating an enlarged structure of interconnected tubes. Branching morphogenesis has been studied extensively in animals and much has been learned about the regulation of branching at the cellular and molecular level. Here, we discuss studies of the Drosophila trachea and of the vertebrate vasculature, which have revealed how new branches are formed and connect (anastomose), leading to the establishment of complex tubular networks. We briefly describe the cell behaviour underlying tracheal and vascular branching. Although similar at many levels, the branching and anastomosis processes characterized thus far show a number of differences in cell behaviour, resulting in somewhat different tube architectures in these two organs. We describe the similarities and the differences and discuss them in the context of their possible developmental significance. We finish by highlighting some old and new data, which suggest that live imaging of the development of capillary beds in adult animals might reveal yet unexplored endothelial behaviour of endothelial cells.
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