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 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.
Department of Internal Medicine D, University of Münster, Münster, Germany.
Giovana Seno
GS
Di Marco
Maximilian
M
König
Christian
C
Stock
Anne
A
Wiesinger
Uta
U
Hillebrand
Stefanie
S
Reiermann
Stefan
S
Reuter
Susanne
S
Amler
Gabriele
G
Köhler
Friedrich
F
Buck
Manfred
M
Fobker
Philipp
P
Kümpers
Hans
H
Oberleithner
Martin
M
Hausberg
Detlef
D
Lang
Hermann
H
Pavenstädt
Marcus
M
Brand
D000818:Animals; D017306:Annexin A2 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D017209:Apoptosis; D002465:Cell Movement; D002478:Cells, Cultured; D002642:Chick Embryo; D015536:Down-Regulation; D006801:Humans; D054559:Hyperphosphatemia / Q000503:physiopathology*; D008297:Male; D018919:Neovascularization, Physiologic; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000150:complications; D059289:Vascular Stiffness
D017306:Annexin A2