The use of small molecules to illuminate vascular development

Development of the vascular system is a multifactorial process. Its proper establishment has a big impact on life. Not only is this process essential for organismal growth but abnormal blood vessel formation leads to several pathologies. In some cases the disease itself triggers changes to the vascular system. I have worked on three aspects regarding the development of the vascular system: drugs inhibiting the formation of new sprouting vessels (angiogenic vessels), vascular patterning, and its stability. I have used small molecules to probe these processes. First, I showed the advantage of using zebrafish as a model system for efficiently screening anti-angiogenic small molecule compounds designed for cancer therapy. Treating cancer by inhibiting its recruitment of new blood vessels prevents nutrients from reaching the growing tumor. Of 11 novel potential compounds tested, I identified 5 with anti-angiogenic properties, all likely inhibiting the Vascular endothelial growth factor (Vegf) pathway, and showed that these compounds have different effects and efficacies. However, blood vessel patterning cues and mechanisms differ in different organs. In order to design more effective therapies, I next investigated the development of the intestinal vasculature, a poorly characterized vascular bed. By using small molecule inhibitors, I found that both Vegf and Bone morphogenetic protein (Bmp) signaling drive the growth and patterning of this plexus. A genetic mutant with overgrowth of the intestinal vasculature follows similar growth cues, but development is faster and unrestricted. Finally, I have investigated a later aspect of blood vessel development: vascular stability. By interacting with mural cells, endothelial cells mature into a functional apparatus that delivers nutrients, collects waste, responds to inflammation, and regulates blood pressure. The nkx3.2 transcription factor was downregulated in two models of vascular instability. I found that Nkx3.2 contributes to vascular stability as its knockout reduces the number of mural cells, and that mutant embryos are more likely to hemorrhage after treatment with a drug affecting mural-endothelial cell contact. Through this work I have increased our knowledge of vascular development and stabilization through detailed understanding of early vessel formation and the use of small molecules.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Biochemistry and Molecular Biology

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2017

Author dc:creator

• Goi, Michela

Advisor dc:contributor.advisor

• Childs, Sarah J

• Genetics
• Biology--Molecular

Statement dc:rights

• University 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.

Language dc:language.iso

eng

DOI

http://dx.doi.org/10.11575/PRISM/28414

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:11023/3958