High phosphate directly affects endothelial function by downregulating annexin II

Hyperphosphatemia is associated with increased cardiovascular risk in patients with renal disease and in healthy individuals. Here we tested whether high phosphate has a role in the pathophysiology of cardiovascular events by interfering with endothelial function, thereby impairing microvascular fun...

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Bibliographic Details
Published in:Kidney international 2013-02, Vol.83 (2), p.213-222
Main Authors: Di Marco, Giovana Seno, König, Maximilian, Stock, Christian, Wiesinger, Anne, Hillebrand, Uta, Reiermann, Stefanie, Reuter, Stefan, Amler, Susanne, Köhler, Gabriele, Buck, Friedrich, Fobker, Manfred, Kümpers, Philipp, Oberleithner, Hans, Hausberg, Martin, Lang, Detlef, Pavenstädt, Hermann, Brand, Marcus
Format: Article
Language:English
Subjects:
angiogenesis
Animals
Annexin A2 - analysis
Annexin A2 - antagonists & inhibitors
Annexin A2 - physiology
annexin II
Apoptosis
Cell Movement
Cells, Cultured
Chick Embryo
chronic kidney disease
Down-Regulation
endothelial cells
Humans
hyperphosphatemia
Hyperphosphatemia - physiopathology
Male
Neovascularization, Physiologic
Proteomics
Rats
Rats, Sprague-Dawley
Renal Insufficiency, Chronic - complications
Vascular Stiffness
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Summary:Hyperphosphatemia is associated with increased cardiovascular risk in patients with renal disease and in healthy individuals. Here we tested whether high phosphate has a role in the pathophysiology of cardiovascular events by interfering with endothelial function, thereby impairing microvascular function and angiogenesis. Protein expression analysis found downregulation of annexin II in human coronary artery endothelial cells, an effect associated with exacerbated shedding of annexin II–positive microparticles by the cells exposed to high phosphate media. EAhy926 endothelial cells exposed to sera from hyperphosphatemic patients also display decreased annexin II, suggesting a negative correlation between serum phosphate and annexin II expression. By using endothelial cell–based assays in vitro and the chicken chorioallantoic membrane assay in vivo, we found that angiogenesis, vessel wall morphology, endothelial cell migration, capillary tube formation, and endothelial survival were impaired in a hyperphosphatemic milieu. Blockade of membrane-bound extracellular annexin II with a specific antibody mimicked the effects of high phosphate. In addition, high phosphate stiffened endothelial cells in vitro and in rats in vivo. Thus, our results link phosphate and adverse clinical outcomes involving the endothelium in both healthy individuals and patients with renal disease.
ISSN:0085-2538
1523-1755
DOI:10.1038/ki.2012.300