The use of small molecules to illuminate vascular development
Abstract
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.
Description
Keywords
Genetics, Biology--Molecular
Citation
Goi, M. (2017). The use of small molecules to illuminate vascular development (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28414