Effects of Phosphate on Vascular Function Under Normal Conditions and Influence of the Uraemic State

Cardiovasc Res. 2012 Oct 1;96(1):130-9. doi: 10.1093/cvr/cvs240. Epub 2012 Jul 20.

Abstract

Aims: Increased serum phosphorus levels are associated with cardiovascular disease in patients with chronic kidney disease (CKD) and in the general population. High phosphate levels may play a direct role in vascular dysfunction. We investigated here the effects of phosphate loading and of the phosphate binder sevelamer-HCl on vascular function.

Methods and results: CKD and non-CKD C57/BL6 mice were used to study the effects of CKD, phosphate, and sevelamer-HCl on vascular function and structure. In vitro, phosphate exhibited a direct vasoconstrictor effect on aortic rings. This effect was smaller in vessels from CKD than non-CKD mice and it was abolished by reactive oxygen species inhibitor dimethylthiourea. A high-phosphate diet (1.3%) increased phenylephrine-induced contraction and lowered acetylcholine-induced relaxation of aortic rings ex vivo, both in non-CKD and CKD mice. It also induced endothelial cell detachment. Sevelamer-HCl exposure in vitro normalized the endothelial dysfunction induced by 3.0 mM phosphate and restored endothelial integrity. Sevelamer-HCl treatment of CKD mice under normal diet (0.65% phosphate) improved the endothelial dysfunction, aortic systolic expansion rate, and pulse wave velocity, and it reduced the endothelial expression of adhesion molecules.

Conclusion: Changes in extracellular phosphorus concentrations may directly modulate vascular function and thereby modulate the vascular smooth muscle response to physiological or pathological stimuli in normal and CKD mice. Whether serum phosphorus lowering and/or dietary phosphate restriction can improve arterial function in humans remains to be established.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chelating Agents / therapeutic use
  • Disease Models, Animal
  • Endothelium, Vascular / physiopathology
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Heart Diseases / etiology*
  • Heart Diseases / prevention & control
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Hyperphosphatemia / etiology
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Smooth Muscle / drug effects
  • Phosphates / blood*
  • Phosphorus, Dietary / adverse effects
  • Polyamines / therapeutic use
  • Pulse Wave Analysis
  • Reactive Oxygen Species / metabolism
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / complications*
  • Renal Insufficiency, Chronic / physiopathology
  • Sevelamer
  • Uremia / blood
  • Uremia / complications*
  • Uremia / physiopathology
  • Vascular Diseases / etiology*
  • Vascular Diseases / prevention & control

Substances

  • Chelating Agents
  • Phosphates
  • Phosphorus, Dietary
  • Polyamines
  • Reactive Oxygen Species
  • Sevelamer
  • Extracellular Signal-Regulated MAP Kinases