Mechanisms of inorganic phosphate-induced vascular calcification in primary human aortic smooth muscle cells

Abstract

Vascular calcification (VC) is commonly associated with aging, atherosclerosis, metabolic syndrome, and chronic kidney disease (CKD). VC involves the transformation of vascular smooth muscle cells (VSMCs) into an osteoblastic phenotype, leading to mineralisation. Key transcription factors like runt-related transcription factor 2 (RUNX2), also known as core-binding factor subunit α-1 (CBF- α-1), are upregulated in this process. Bone matrix-related proteins, including osteoprotegerin, osteopontin, and sclerostin (SOST), activate multiple cellular signalling pathways promoting VC. Establishing a reliable VC model is crucial for understanding the underlying mechanisms and developing potential therapeutic interventions. Although cannabidiol (CBD), a natural compound derived from cannabis, has emerged as a potential therapeutic agent for managing cardiovascular diseases, its full efficacy in reducing VC has not been sufficiently investigated. The first aim of this study was to establish a VC model using human aortic smooth muscle cells (HASMCs) and explore the potential role of bone-related proteins, especially SOST, in the development and progression of VC, as discussed in Chapter 2. The second aim was to assess the differential expression of proteins in the VC cellular model, as detailed in Chapter 3. The third aim was to investigate whether CBD can inhibit the transition of HASMCs into osteoblastic phenotype cells by modulating signalling mediated by bone matrix-related protein. This study demonstrates that elevated phosphate levels directly stimulate HASMCs to undergo phenotypic changes, predisposing them to calcification. Although CBD treatment was associated with increased calcium deposits, indicating a complex role in the calcification process, these findings highlight the necessity for further investigation into the effects of CBD on VC. The study provides valuable insights into the regulatory mechanisms of VC, emphasising the significance of bone-related proteins in its development. These findings enhance the understanding of VC in cardiovascular diseases and underscore the need for continued research to explore the therapeutic potential of CBD and related natural products in vascular health.

Date of Thesis submission	2025
Original language	English
Awarding Institution	Western Sydney University
Supervisor	Mitchell Low (Supervisor), Dennis Chang (Supervisor), Chun Guang Li (Supervisor), Deep Bhuyan (Supervisor) & Sai-Wang Seto (Supervisor)