Endothelial : mural cell interplay in regulation of blood- and lymph vessel development and function
Author: Wang, Yixin
Date: 2018-01-19
Location: Lecture Hall Hillarp, Retzius Väg 8, Karolinska Institutet, Solna
Time: 09.30
Department: Inst för medicinsk biokemi och biofysik / Dept of Medical Biochemistry and Biophysics
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Thesis (1.273Mb)
Abstract
Blood- and lymphatic vascular development and homeostasis depend on correct endothelial-mural cell interaction, and dysregulation thereof is apparent in multiple human diseases. However the mechanisms controlling the formation of these respective vascular systems are not fully understood. Previously, the binding of EC-derived Platelet derived growth factor B (PDGFB) to its receptor, PDGFRβ on mural cells, was shown to play an important role in recruitment of mural cells to blood capillaries. Whether PDGFB carries similar functions in the lymphatic vasculature is still unclear. In addition, potential regulation of PDGFRβ signalling by other PDGFs, in the context of endothelial-mural cell interaction, is not fully understood.
This thesis focuses on PDGFRβ signalling, mediated by PDGFB and PDGFD, in regulation of endothelial-mural cell interplay in blood and lymphatic vessel development. By generation of several genetic modified mouse models, including inducible targeting of PDGFB in the lymphatic endothelium, we reveal that PDGFB is required for recruitment of smooth muscle cells (SMCs) to collecting lymphatic vessels. In addition we show that SMCs play no major role in the establishment of lymphatic vessel identities but that these cells are responsible for the recorded pulsatile contraction of dermal collecting vessels. Furthermore, our data suggest that it is unlikely that pathological SMC recruitment to capillaries is caused by altered PDGFB expression alone, but that it also relies on extra cellular matrix composition. Besides PDGFB, we also demonstrated a potential involvement of PDGFD in regulation of EC-pericyte interplay. We found that, although PDGFB and PDGFD evoked similar PDGFRβ activation, these ligands promoted differential pericyte behavioural responses in 3-dimesional angiogenesis assays. This may be related to our discovery of an interaction between PDGFD and Neuropilin-1 (NRP1).
A part of this thesis was also dedicated to record vascular development from a new level of both imaging and time resolution. By using the wounded mouse cornea as a live imaging site, we developed an in vivo imaging approach that allows for documentation of vascular morphogenesis over time, at subcellular resolution. We used this method to analyse EC migratory behaviour and highlighted directional migration against blood flow. We also characterized vessel patterning with respect to mural cell distribution during sprouting angiogenesis in the inflamed cornea. Furthermore, we recorded temporal and spatial aspects of VEGFA-induced vessel permeability by intra vital live imaging and revealed distinct artery-venous properties.
Taken together, this thesis contributes to the understanding of the roles of endothelial- and mural cells in the context of blood and lymphatic vascular development. Our findings shed new light on mechanisms regulating cardiovascular homeostasis in development and disease.
This thesis focuses on PDGFRβ signalling, mediated by PDGFB and PDGFD, in regulation of endothelial-mural cell interplay in blood and lymphatic vessel development. By generation of several genetic modified mouse models, including inducible targeting of PDGFB in the lymphatic endothelium, we reveal that PDGFB is required for recruitment of smooth muscle cells (SMCs) to collecting lymphatic vessels. In addition we show that SMCs play no major role in the establishment of lymphatic vessel identities but that these cells are responsible for the recorded pulsatile contraction of dermal collecting vessels. Furthermore, our data suggest that it is unlikely that pathological SMC recruitment to capillaries is caused by altered PDGFB expression alone, but that it also relies on extra cellular matrix composition. Besides PDGFB, we also demonstrated a potential involvement of PDGFD in regulation of EC-pericyte interplay. We found that, although PDGFB and PDGFD evoked similar PDGFRβ activation, these ligands promoted differential pericyte behavioural responses in 3-dimesional angiogenesis assays. This may be related to our discovery of an interaction between PDGFD and Neuropilin-1 (NRP1).
A part of this thesis was also dedicated to record vascular development from a new level of both imaging and time resolution. By using the wounded mouse cornea as a live imaging site, we developed an in vivo imaging approach that allows for documentation of vascular morphogenesis over time, at subcellular resolution. We used this method to analyse EC migratory behaviour and highlighted directional migration against blood flow. We also characterized vessel patterning with respect to mural cell distribution during sprouting angiogenesis in the inflamed cornea. Furthermore, we recorded temporal and spatial aspects of VEGFA-induced vessel permeability by intra vital live imaging and revealed distinct artery-venous properties.
Taken together, this thesis contributes to the understanding of the roles of endothelial- and mural cells in the context of blood and lymphatic vascular development. Our findings shed new light on mechanisms regulating cardiovascular homeostasis in development and disease.
List of papers:
I. Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity. Yixin Wang, Yi Jin, Maarja Andaloussi Mäe, Yang Zhang, Henrik Ortsäter, Christer Betsholtz, Taija Mäkinen, Lars Jakobsson. Development. (2017) 144, 3590-3601.
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II. Characterization of multi-cellular dynamics of angiogenesis and vascular remodelling by intravital imaging of the wounded mouse cornea. Yixin Wang, Yi Jin, Bàrbara Laviña and Lars Jakobsson. [Submitted]
III. Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D–PDGFRβ signaling. Lars Muhl, Erika Bergsten Folestad, Hanna Gladh, Yixin Wang, Christine Moessinger, Lars Jakobsson and Ulf Eriksson. Journal of Cell Science. (2017) 130, 1365-1378.
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View record in Web of Science®
I. Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity. Yixin Wang, Yi Jin, Maarja Andaloussi Mäe, Yang Zhang, Henrik Ortsäter, Christer Betsholtz, Taija Mäkinen, Lars Jakobsson. Development. (2017) 144, 3590-3601.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Characterization of multi-cellular dynamics of angiogenesis and vascular remodelling by intravital imaging of the wounded mouse cornea. Yixin Wang, Yi Jin, Bàrbara Laviña and Lars Jakobsson. [Submitted]
III. Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D–PDGFRβ signaling. Lars Muhl, Erika Bergsten Folestad, Hanna Gladh, Yixin Wang, Christine Moessinger, Lars Jakobsson and Ulf Eriksson. Journal of Cell Science. (2017) 130, 1365-1378.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Jakobsson, Lars
Co-supervisor: Eriksson, Ulf
Issue date: 2017-12-21
Rights:
Publication year: 2017
ISBN: 978-91-7676-916-4
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