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The anatomical and molecular characterisation of vascular ingression in the embryonic vertebrate brain

Student thesis: Doctoral Thesis

The vascularisation of the embryonic brain is a dynamic process governed by an intricate network of regulatory pathways. The process of vascularisation has been studied in the spinal cord of avian embryos but very little work has been conducted in the rostral brain. The present study therefore aimed to characterise the major events involved in the vascularisation of the Gallus gallus brain, with supporting work conducted in Xenopus laevis. Endothelial cells migrated from the mesoderm towards the brain, leading to the formation of the perineural vascular plexus. Endothelial sprouts invaded the brain, which then branched and fused to form the intraneural vascular plexus. Cell replication was also detected throughout the process. A similar sequence of events have previously been described in quail and mouse, providing support for an evolutionarily conserved process throughout vertebrate evolution.
Matrix metalloproteinases play a major role in remodelling the extracellular matrix, which is an essential aspect in angiogenesis. MMPs -1, -2 and -9 were expressed within the perineural vascular plexus, differentially within the invading sprouts and also in the intraneural vascular plexus. Gelatinase activity was also detected in specific cells within the perineural vascular plexus and in the invading sprouts. Altering the level of MMP activity lead to the formation of endothelial cell clusters, which may have resulted from defective proliferation and migration. The results provide a novel contribution to the role of MMPs in brain vascularisation.
The brain plays an important role in organising its vasculature, therefore the influence of neural tube patterning on ingression was investigated. The ectopic expression of the ventralising signal, sonic hedgehog, expanded the perineural vascular plexus and disrupted sprout formation. Lowering Notch activity lead to a significant increase in the number of endothelial cells within the brain. Endothelial cell clusters were formed, suggesting that Notch may also play a role in maintaining the structural integrity of vessel sprouts. The arrangement of the sprout, with a leading tip cell and follower stalk cells, is reminiscent of invasion by certain cancers. The process of endothelial ingression may therefore share similarities with tumour angiogenesis and could aid in developing novel strategies for reducing tumourigenesis and for stroke recovery.
Original languageEnglish
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Award dateMay 2017

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