Development of Rasa1 arteriovenous malformations

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dc.contributor.advisorChilds, Sarah
dc.contributor.authorGreysson-Wong, Jasper
dc.contributor.committeememberBrook, William
dc.contributor.committeememberHuang, Peng
dc.contributor.committeememberKurek, Kyle
dc.contributor.committeememberFish, Jason
dc.date2023-02
dc.date.accessioned2023-01-06T20:47:35Z
dc.date.available2023-01-06T20:47:35Z
dc.date.issued2022-12-22
dc.description.abstractPrecise regulation of signalling is critical to ensure proper formation of blood vessel networks during development. Mutations in key genes may disturb this finely tuned process, resulting in malformed vessels. Mutations in RASA1, a Ras GTPase activating protein, leads to the development of arteriovenous malformations (AVMs), where arteries are connected directly to veins without interceding capillary beds. Using zebrafish, I show that rasa1 mutants also develop AVMs in their tail vasculature, which subsume the posterior of the dorsal aorta and caudal venous plexus. The development of rasa1 AVMs does not depend on flow and modulating flow does not prevent or rescue AVM formation. However, blood flow slows in the cavernous AVM, changing flow-responsive signalling reducing expression of flow responsive transcription factor klf2a. Incomplete remodelling of the caudal venous plexus is visualized by an excess of residual intraluminal pillars, an indication of impaired intussusceptive angiogenesis. I show that AVM development is dependant on venous activation of MEK/ERK signalling and that inhibition of MEK signalling can prevent AVM development during an early developmental window, but MEK inhibition cannot rescue an AVM that has already formed. For the first time, I show that Bmp and Vegf signalling both play a role in AVM development, pathways that are important in other vascular malformations but had yet to be explored in RASA1 models.en_US
dc.identifier.citationGreysson-Wong, J. (2023). Development of Rasa1 arteriovenous malformations (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.urihttp://hdl.handle.net/1880/115652
dc.identifier.urihttps://dx.doi.org/10.11575/PRISM/40578
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
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.en_US
dc.subjectdevelopmental biologyen_US
dc.subjectvascular developmenten_US
dc.subjectdisease modelen_US
dc.subjectrasa1en_US
dc.subjectarteriovenous malformationen_US
dc.subjectcapillary malformationen_US
dc.subjectblood vessel developmenten_US
dc.subjectzebrafishen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationBiology--Molecularen_US
dc.subject.classificationBiochemistryen_US
dc.titleDevelopment of Rasa1 arteriovenous malformationsen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineMedicine – Biochemistry and Molecular Biologyen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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