Determining Genetic Mechanisms of Vascular Stability: A Novel Role For FoxF2

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atmire.migration.oldid4779
dc.contributor.advisorChilds, Sarah
dc.contributor.authorArnold, Corey
dc.contributor.committeememberGrewal, Savraj
dc.contributor.committeememberMcGhee, James
dc.contributor.committeememberAppel, Bruce
dc.contributor.committeememberGordon, Grant
dc.date.accessioned2016-08-25T21:22:23Z
dc.date.available2016-08-25T21:22:23Z
dc.date.issued2016
dc.date.submitted2016en
dc.description.abstractEndothelial cells of blood vessels interact with surrounding peri-endothelial cells (pericytes and vascular smooth muscle cells) to maintain integrity, modulate blood flow and promote homeostasis, collectively contributing to vascular stability. Both the initial establishment and subsequent maintenance of vascular stability is crucial to the integrity of the vasculature, and loss of this support can result in hemorrhage. Hemorrhagic events in brain vessels often lead to stroke, and accumulation of vascular insults originating from small brain vessels and capillaries, known as cerebral small vessel disease, can cause cognitive decline in addition to stroke. The identification of genetic factors promoting vascular stability is therefore fundamental to our understanding of cerebral vessel function in development and disease. Through microarray expression profiling of a genetic zebrafish model of cerebral hemorrhage, I found the transcription factor FoxF2 to be significantly downregulated. With further investigation, I discovered a novel role for FoxF2 in zebrafish cerebral vascular stability, both developmentally and in later stages of life. I show that transient knockdown and genetic knockout of the zebrafish FoxF2b paralog results in vascular stability defects during development. Furthermore, I provide evidence that FoxF2 is expressed in neural crest- and ventral mesoderm-derived head mesenchyme, and promotes differentiation of vascular smooth muscle and pericytes potentially through modulation of vascular stability-related signaling pathways. In the adult zebrafish brain, I find that FoxF2 is specifically expressed in pericytes and genetic knockout results in brain hemorrhages. These findings parallel recent observations of human FoxF2 mutations, which exhibit hallmarks of cerebral small vessel disease. Genetic variants in a potential regulatory region of human FoxF2 have been also recently been linked to stroke, further suggesting a role for FoxF2 as a human disease gene. Through this work, I have identified a potential mechanism by which FoxF2 promotes cerebral vascular stability and paved the way for future investigations of cerebral vascular development and disease.en_US
dc.identifier.citationArnold, C. (2016). Determining Genetic Mechanisms of Vascular Stability: A Novel Role For FoxF2 (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25608en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/25608
dc.identifier.urihttp://hdl.handle.net/11023/3223
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology--Cell
dc.subjectGenetics
dc.subjectBiology--Molecular
dc.subject.classificationVascular Stabilityen_US
dc.subject.classificationVascular Smooth Muscleen_US
dc.subject.classificationPericyteen_US
dc.subject.classificationFoxF2en_US
dc.subject.classificationzebrafishen_US
dc.titleDetermining Genetic Mechanisms of Vascular Stability: A Novel Role For FoxF2
dc.typedoctoral thesis
thesis.degree.disciplineBiochemistry and Molecular Biology
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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