Hyaluronan (HA)-regulation of vascular smooth muscle cell phenotype and vascular calcification in chronic kidney disease

Roy, Shrea 2023. Hyaluronan (HA)-regulation of vascular smooth muscle cell phenotype and vascular calcification in chronic kidney disease. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Vascular calcification (VC) is a powerful predictor of cardiovascular mortality and is prevalent among patients with chronic kidney disease (CKD), including those on dialysis, yet it lacks effective treatment. It can occur in two anatomical locations: intimal and medial layers. The transformation of vascular smooth muscle cells (VSMCs) into an osteoblastic phenotype within arterial walls is a key factor in the development of medial VC. Previous research has shown that the glycosaminoglycan hyaluronan (HA) in the extracellular matrix plays a vital role in cell phenotype regulation, in the contexts of cancer biology, stem cell biology, and epithelial-mesenchymal transition. While previous studies have shown increased expression of HA in non-CKD related VC, its role in controlling VSMC phenotype and osteogenic differentiation has not been explored. This study aimed to investigate the role of HA in medial calcification. Both in vivo and in vitro models of medial calcification revealed a decrease in HA levels during VSMC osteogenic differentiation. Experiments involving HA degradation indicated that HA has an inhibitory effect on calcification. Additionally, the study examined HA-binding proteins such as TSG-6 and Versican, uncovering their roles in modulating HA and influencing VSMC differentiation. The research emphasized the significance of HAS isoenzymes in HA synthesis, with HAS1 and HAS2 overexpression demonstrating protective effects against calcification. However, HAS3 displayed complex effects on calcification, necessitating further exploration. Inflammation plays a pivotal role in VC associated with CKD-related cardiovascular disease. In both in vivo and in vitro inflammation models, increased HA expression was observed, aligning with previous findings in atherosclerosis. Moreover, the study identified altered expression patterns of HA-binding proteins under inflammatory conditions. In summary, this research illuminates the role of HA and its associated proteins in arterial calcification within CKD. It suggests that certain forms of HA in the media may have a protective effect, whereas consistently in the intima, HA is associated with exacerbated disease. This underscores the significance of specific HA-binding proteins and underscores the need for further investigation into the intricate interplay between inflammation and calcification in CKD-related cardiovascular disease.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	1 March 2024
Last Modified:	01 Mar 2024 09:33
URI:	https://orca.cardiff.ac.uk/id/eprint/166727

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