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

Date
2016
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Abstract
Endothelial 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.
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Keywords
Biology--Cell, Genetics, Biology--Molecular
Citation
Arnold, 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/25608