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CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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(English)Manuscript (preprint) (Other academic)
Keyword [en]
Angiogenesis, vascular morphogenesis, cerebrovascular malformation, endothelial cells, CDC42, MEKK3 signaling, KLF2/4
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-347776OAI: oai:DiVA.org:uu-347776DiVA, id: diva2:1195803
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2018-04-09Bibliographically approved
In thesis
1. Cellular and molecular roles for CDC42 in angiogenesis
Open this publication in new window or tab >>Cellular and molecular roles for CDC42 in angiogenesis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis is the physiological process by which new blood vessels grow and critically depends on the interplay between the major vascular units: endothelial cells, pericytes and smooth muscle cells. Dysfunction and mispatterning of blood vessels are associated with the progression of many vascular complications, and therefore, understanding the causes of vascular dysmorphia is a central question in vascular biology. CDC42 is a small GTPase known to regulate a diverse array of cellular functions in endothelial cells, however, its contribution to vascular development in vivo remains incompletely understood. The overall aim of this thesis work is to investigate the role of CDC42 during angiogenesis in the central nervous system, using an inducible endothelial-specific Cdc42 knockout model.

In Paper I, I investigate which CDC42-dependent functions operational in vivo are of relevance for angiogenic sprouting, and how they contribute to blood vessel morphogenesis. Analysis of distinct cellular behaviours shows that CDC42 is critically required for proper EC dispersion in the vasculature and that it regulates sprouting angiogenesis and endothelial axial polarity.

In Paper II, I explore the in vivo consequences of Cdc42 deletion for vascular morphogenesis, leading to the appearance of capillary-venous malformations in the brain, resembling the human disease of cerebral cavernous malformations. I aimed to understand how this type of vascular malformations arise and was been able to identify the MEKK3-ERK5-KLF2/4 molecular signalling pathway and other cellular events as the trigger factors that may be responsible for these malformations.

Paper III redirects focus to the physiological roles of another protein, GPR116, in modulating blood-brain barrier permeability and pathologic angiogenesis in the central nervous system.

In summary, these findings reveal crucial roles of endothelial CDC42 during angiogenesis and further uncover its potential relevance in the molecular pathogenesis of cerebrovascular malformations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 52
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1458
Keyword
CDC42, angiogenesis, endothelial cell, vascular malformation
National Category
Cell and Molecular Biology
Research subject
Biology with specialization in Molecular Cell Biology
Identifiers
urn:nbn:se:uu:diva-347778 (URN)978-91-513-0317-8 (ISBN)
Public defence
2018-06-02, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2018-05-04 Created: 2018-04-07 Last updated: 2018-05-04

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Castro, MarcoLaviña, BàrbaraAndo, KojiDejana, ElisabettaBetsholtz, ChristerGängel, Konstantin

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Vascular BiologyDepartment of Immunology, Genetics and Pathology
Cell and Molecular Biology

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