uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations
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.
VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Leuven, Belgium; Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium.
Show others and affiliations
2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 13, article id UNSP dev161182Article in journal (Refereed) Published
Abstract [en]

Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

Place, publisher, year, edition, pages
2018. Vol. 145, no 13, article id UNSP dev161182
Keywords [en]
Vascular malformations, Cdc42, Cell migration, Endothelial axial polarity, Angiogenesis, Proliferation
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-361537DOI: 10.1242/dev.161182ISI: 000439224400008PubMedID: 29853619OAI: oai:DiVA.org:uu-361537DiVA, id: diva2:1252222
Funder
Swedish Research Council, VR2015-00550EU, European Research Council, 2011-294556EU, European Research Council, EU-ERC269073Knut and Alice Wallenberg Foundation, 2012.0272EU, FP7, Seventh Framework Programme, 317250Swedish Cancer Society, CAN2015/771The Wenner-Gren FoundationAvailable from: 2018-10-01 Created: 2018-10-01 Last updated: 2020-03-19Bibliographically approved
In thesis
1. Cdc42, orchestrator of vascular morphogenesis in the retina
Open this publication in new window or tab >>Cdc42, orchestrator of vascular morphogenesis in the retina
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cdc42 is a small GTPase that controls many cellular functions related to cytoskeletal dynamics, such as migration, polarity, and proliferation. Despite what we know of Cdc42 in other cell types, not much research has been done on the vasculature. This thesis describes the consequences of Cdc42 deletion in two vascular cell types—endothelial and mural cells—during developmental angiogenesis.

In paper I, we demonstrate through a combination of in vitro, in silico, and in vivo assays, that Cdc42-deficient endothelial cells migrate less and fail to distribute normally in areas of naturally occurring high proliferation during angiogenesis, causing vascular malformations with enlarged lumens. In addition, these cells present impaired filopodia formation, a disadvantage for the tip cell position, disturbed axial polarity and altered junctions.

With an in vivo approach, in paper III we demonstrate that the deletion of Cdc42 in mural cells has consequences on the morphogenesis of the retinal vasculature. Cdc42-deficient mural cells proliferate less and cannot keep up with the nascent angiogenic vasculature, which results in a complete pericyte loss at the sprouting front. Furthermore, we describe that mural cells contribute to the remodeling of the vasculature, also after the initial phases of angiogenesis.

The CreERT2 system is frequently used for conditional gene deletion and lineage tracing. Tamoxifen administration allows spatiotemporally controlled recombination of fluorescent reporters, and tracing of the labeled cells. However, in the course of our studies, we observed tamoxifen-independent recombination. In paper II, we describe this phenomenon in detail, using different combinations of CreERT2 and fluorescent reporter lines. We conclude that tamoxifen-independent recombination is a widespread occurrence, and that fluorescent reporter lines present varying levels of susceptibility to it.

In summary, the work presented here sheds new light on the role of Cdc42 in the vasculature. Additionally, this thesis describes in detail an important feature of CreERT2 and reporter lines that should be taken into account when performing lineage-tracing experiments.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 48
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1653
Keywords
Cdc42, endothelial cell, pericyte, mural cell, angiogenesis, CreERT2
National Category
Developmental Biology Genetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-407117 (URN)978-91-513-0910-1 (ISBN)
Public defence
2020-05-15, Rudbecksalen, Dag Hammarskjölds Väg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2020-04-23 Created: 2020-03-19 Last updated: 2020-05-19

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Laviña, BàrbaraCastro, MarcoNiaudet, ColinÁlvarez-Aznar, AlbertoBentley, KatieBetsholtz, ChristerGängel, Konstantin

Search in DiVA

By author/editor
Laviña, BàrbaraCastro, MarcoNiaudet, ColinÁlvarez-Aznar, AlbertoBentley, KatieBrakebusch, CordBetsholtz, ChristerGängel, Konstantin
By organisation
Vascular Biology
In the same journal
Development
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 106 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf