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Cellular and molecular roles for CDC42 in angiogenesis
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Fritextbeskrivning
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. , s. 52
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1458
Emneord [en]
CDC42, angiogenesis, endothelial cell, vascular malformation
HSV kategori
Forskningsprogram
Biologi med inriktning mot molekylär cellbiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-347778ISBN: 978-91-513-0317-8 (tryckt)OAI: oai:DiVA.org:uu-347778DiVA, id: diva2:1195927
Disputas
2018-06-02, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 10:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-05-04 Laget: 2018-04-07 Sist oppdatert: 2018-05-04
Delarbeid
1. Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations: Cdc42 and vascular malformations
Åpne denne publikasjonen i ny fane eller vindu >>Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations: Cdc42 and vascular malformations
Vise andre…
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Emneord
Vascular malformations, Cdc42, cell migration, planar-cell-polarity, angiogenesis, proliferation
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-347774 (URN)
Tilgjengelig fra: 2018-04-06 Laget: 2018-04-06 Sist oppdatert: 2018-04-09bibliografisk kontrollert
2. CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression
Åpne denne publikasjonen i ny fane eller vindu >>CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression
Vise andre…
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Emneord
Angiogenesis, vascular morphogenesis, cerebrovascular malformation, endothelial cells, CDC42, MEKK3 signaling, KLF2/4
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-347776 (URN)
Tilgjengelig fra: 2018-04-06 Laget: 2018-04-06 Sist oppdatert: 2018-04-09bibliografisk kontrollert
3. Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium
Åpne denne publikasjonen i ny fane eller vindu >>Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium
Vise andre…
2015 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 9, artikkel-id e0137949Artikkel i tidsskrift (Fagfellevurdert) 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.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-265915 (URN)10.1371/journal.pone.0137949 (DOI)000361792100023 ()26394398 (PubMedID)
Forskningsfinansiär
EU, European Research Council, 294556EU, European Research Council, ITN-2012-317250-VESSELSwedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg Foundation
Tilgjengelig fra: 2015-11-04 Laget: 2015-11-04 Sist oppdatert: 2018-04-07

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