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Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium
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. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
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.
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0137949Article in journal (Refereed) Published
Abstract [en]

Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysemalike pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.

Place, publisher, year, edition, pages
2015. Vol. 10, no 9, article id e0137949
National Category
Immunology in the medical area Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-265915DOI: 10.1371/journal.pone.0137949ISI: 000361792100023PubMedID: 26394398OAI: oai:DiVA.org:uu-265915DiVA, id: diva2:867036
Funder
EU, European Research Council, 294556EU, European Research Council, ITN-2012-317250-VESSELSwedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2015-11-04 Created: 2015-11-04 Last updated: 2018-04-07
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)
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Supervisors
Available from: 2018-05-04 Created: 2018-04-07 Last updated: 2018-05-04

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Niaudet, ColinHofmann, Jennifer J.Mae, Maarja A.Jung, BongnamGängel, KonstantinVanlandewijck, MichaelAl Sayegh, SaharHe, LiqunCastro Freire, MarcoLavina Siemsen, BarbaraBetsholtz, Christer

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Niaudet, ColinHofmann, Jennifer J.Mae, Maarja A.Jung, BongnamGängel, KonstantinVanlandewijck, MichaelAl Sayegh, SaharHe, LiqunCastro Freire, MarcoLavina Siemsen, BarbaraBetsholtz, Christer
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Vascular BiologyDepartment of Immunology, Genetics and Pathology
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Immunology in the medical areaCardiac and Cardiovascular Systems

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