Vascular calcification maladaptively participates in acute phosphate homeostasis. Issue 4 (3rd October 2022)

• Record Type: Journal Article
• Authors: Turner, Mandy E; Rowsell, Tyler S; Lansing, Austin P; Jeronimo, Paul S; Lee, Lok Hang; Svajger, Bruno A; Zelt, Jason G E; Forster, Corey M; Petkovich, Martin P; Holden, Rachel M; Adams, Michael A
• Is Part Of: Cardiovascular research. Volume 119:Issue 4(2023)
• Page Start: 1077
• Page End: 1091
• Publication Date: 2022-10-03
• Subjects: Vascular calcification -- Phosphate -- Chronic kidney disease -- Calciprotein particles -- Mineral bone disorder; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac162
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Non-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. This process is especially relevant in the setting of chronic kidney disease (CKD), where exposure to increased phosphate is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated mineral dysregulation induces pathological accumulation of phosphate causing vascular calcification (VC). Our objective was to determine whether the systemic response to acute phosphate challenges is altered by VC. Methods and results: After bolus phosphate administration, circulating and tissue deposition of this challenge was assessed in two rat models of VC using a radiolabelled phosphate tracer. In an adenine-induced model of CKD (N = 70), animals with VC had a blunted elevation of circulating 33 PO4 following oral phosphate administration ( P < 0.01), and the discordant deposition could be traced to the calcified arteries (11.4 [7.5–13.1] vs.43.0 [35.5–53.7] pmol/ng tissue, P < 0.001). In a non-CKD model of VC, calcification was induced with 0.5 ug/kg calcitriol and then withdrawn (N = 24). New phosphate uptake by the calcified vasculature correlated to the pre-existing burden of calcification ( r = 38, P < 0.001) and was substantially attenuated in the absence of calcification stimulus ( P < 0.01). Phosphate accrual was stimulated by the phosphate challenge and not present to the same degree during passive disposition of circulating phosphate. Further, the form of phosphate that deposited to the vasculature was predominately amorphous inorganic phosphate and not that which was bound in matured calciprotein particles. Conclusions: In the process of calcification, arteries acutely deposit substantial amorphous phosphate while blunting the elevation in the circulation, thereby altering the systemic disposition of phosphate and identifying VC as a participatory mineral homeostatic organ. This study demonstrates the negative vascular consequence of acute fluctuations in circulating phosphate, and supports the importance of phosphate bioavailability and diet management in CKD patients as a mediator of cardiovascular risk. Graphical Abstract: Graphical abstract