Mechanisms of angiogenesis in development and disease
AuthorGrant, Zoe Louise
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-09-09. This item is currently available to University of Melbourne staff and students only, login required.
© 2019 Zoe Louise Grant
The expansion of blood vessel networks by angiogenesis is critical for matching blood supply to the metabolic demands of growing tissues. In adult tissues, blood vessels and the endothelial cells (ECs) that make them generally remain in a quiescent state. However, the reactivation of angiogenesis is a hallmark of a number of diseases including cancer and vision-threatening eye diseases. In the case of eye disease, angiogenesis results in abnormal vascular growth that damages the retina. This abnormal angiogenesis often occurs in response to retinal hypoxia that can arise as a result of excessive retinal vessel regression. Understanding the mechanisms by which blood vessels both grow and regress is therefore important for understanding how vascular diseases arise in the eye. In this thesis, I have used in vivo mouse models of normal and pathological angiogenesis in the retina to examine the molecular and cellular mechanisms that control blood vessel growth and regression. In the first part of my thesis, I investigated the role of the histone acetyltransferase HBO1 in retinal blood vessel growth. Through its histone acetyltransferase activity, HBO1 promotes transcriptionally permissive chromatin and is necessary for cells to change their gene expression patterns, particularly during development. I found that HBO1 was required for the expression of genes and pathways that are upregulated by ECs undergoing angiogenesis. ECs lacking HBO1 failed to undergo directed migration during angiogenesis, resulting in reduced blood vessel production both in the normal retina and in a model of pathological retinal vessel growth. In the second part of this thesis, I examined the role of EC apoptosis in disease-causing blood vessel regression using a model of ischaemic retinopathy. In this model, vessel regression associated with EC apoptosis results in retinal ischaemia, causing a hypoxic response that drives abnormal vessel growth similar to that seen in human eye diseases. I found that blocking EC apoptosis did not prevent vessel regression or the onset of retinal ischaemia. Nonetheless, it completely prevented the loss of ECs from ischaemic areas of the retina. These preserved ECs were capable of rapidly reassembling into a functional vessel network that reduced hypoxia and the subsequent pathological vascular response. Vessel reassembly was not impeded by neutralising VEGFA, suggesting that it is not dependent on high levels of VEGFA produced by the ischaemic retina. Overall, my studies provide new insight into the mechanisms of blood vessel growth and regression and may potentially open new therapeutic avenues for preventing abnormal blood vessel growth in retinal vascular disease.
Keywordsangiogenesis; apoptosis; vessel regression; histone acetylation; HBO1
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References
- Medical Biology - Theses