Todd, Alexandra Frances; (2018) The Role of Angiopoietin-2 in Vascular Calcification. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cardiovascular disease (CVD) is a leading cause of mortality in paediatric patients with chronic kidney disease (CKD), particularly in those undergoing dialysis. One of the earliest events in CVD is endothelial damage, which may result from changes in levels of vascular growth factors that control blood vessel function and stability. Markers of endothelial dysfunction and vascular calcification are observed during CKD, and are documented as early as the first decade of life. Previous research indicates that growth factors controlling blood vessel function and stability are altered in CKD patients; circulating levels of the pro-inflammatory/anti-angiogenic molecule angiopoietin-2 (Angpt2) are notably increased in children on dialysis and correlate with surrogate markers of vascular calcification. I therefore hypothesise that Angpt2 may promote medial calcification in CKD. Through in vitro studies using intact vessel rings and explanted vascular smooth muscle cells (VSMCs) from paediatric pre-dialysis and dialysis patients, I have shown that addition of exogenous Angpt2 in a pro-calcaemic environment (medium supplemented with 2.7 mM calcium, and 2.0 mM phosphate) increases calcium deposition within vessels from dialysis patients, but has no effect on control or predialysis vessels. In endothelial cells, Angpt2 acts through the receptor tyrosine kinase with immunoglobulin-like and EGF-like domains-2 (Tie2); this receptor was detected through immunofluorescence in the media layer of the intact vessels and by protein and RNA analyses of explanted VSMCs. The calcifying effect of Angpt2 in VSMCs could be blocked by downregulating Tie2 expression by small interfering ribonucleic acid (siRNA), but was not prevented by addition of the Angpt2 antagonist, vascular stabiliser and anti-inflammatory molecule, Angpt1. Vascular calcification is driven through several pathophysiological mechanisms including osteogenic gene expression, apoptosis and vesicle release; these have been investigated in both vascular rings and explanted VSMCs. While the full mechanism has yet to be elucidated, this thesis provides evidence to suggest that manipulation of Tie2 and angiopoietin pathways may have potential to decrease the rate of vascular calcification in patients with CKD.

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