Hypophosphatemia-mediated hypotension in transgenic mice overexpressing human FGF-23

1 Laboratory of Reproductive Medicine and The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China; 2 Department of Anatomy, Histology and Embryology, Southeast University, Nanjing, China; and 3 Department of Medicine, McGill University, Montreal, Canada Submitted June 30, 2009 ; accepted in final form August 13, 2009 Fibroblast growth factor-23 (FGF-23) is a potent circulating phosphaturic factor associated with renal phosphate wasting. The effects of FGF-23 on skeletal and phosphate homeostasis have been investigated widely; however, the effect of FGF-23 on the cardiovascular system (CVS) is unknown. To assess whether FGF-23 influences the function and structure of the CVS and whether the effect of FGF-23 on the CVS is mediated by FGF receptors directly or indirectly by hypophosphatemia, FGF-23 transgenic mice and their wild-type littermates were fed a normal diet or a high-phosphate diet comprising a normal diet plus 1.25% phosphate in drinking water from weaning for 5 wk, and the phenotypes of the CVS were compared between FGF-23 transgenic mice and their wild-type littermates on the same diet. At the end of this time period, transgenic animals on the normal diet developed hypotension. The left ventricle was appropriately hypertrophic, and plasma catecholamine and renin-angiotensin system components were upregulated, indicating compensatory mechanisms in response to the hypotension. Transgenic mice also exhibited an impaired vascular reactivity and a downregulation of vasoconstrictor receptor gene expression, possibly as pathogenetic factors contributing to the hypotension. The high-phosphate diet improved the hypophosphatemia, resulting in a rescue of the cardiovascular phenotype. This study demonstrates that FGF-23 overexpression can result in abnormalities in the CVS and that the effect of FGF-23 overexpression on the CVS is mediated by the secondary severe hypophosphatemia. fibroblast growth factor-23; cardiovascular system; blood pressure; phosphaturic factor Address for reprint requests and other correspondence: D. S. Miao, Lab. of Reproductive Medicine, The Research Center for Bone and Stem Cells, Dept. of Anatomy, Histology and Embryology, Nanjing Medical Univ., Nanjing, P. R. China (e-mail: dsmiao{at}njmu.edu.cn ).