title: FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability.
abstract: Fibroblast growth factor 23 (FGF23) is secreted primarily by osteocytes and regulates phosphate and vitamin D metabolism. Elevated levels of FGF23 are clinically associated with endothelial dysfunction and arterial stiffness in chronic kidney disease (CKD) patients; however, the direct effects of FGF23 on endothelial function are unknown. We hypothesized that FGF23 directly impairs endothelial vasorelaxation by hindering nitric oxide (NO) bioavailability. We detected expression of all four subtypes of FGF receptors (Fgfr1-4) in male mouse aortas. Exogenous FGF23 (90-9,000 pg/ml) did not induce contraction of aortic rings and did not relax rings precontracted with PGF2α. However, preincubation with FGF23 (9,000 pg/ml) caused a ∼36% inhibition of endothelium-dependent relaxation elicited by acetylcholine (ACh) in precontracted aortic rings, which was prevented by the FGFR antagonist PD166866 (50 nM). Furthermore, in FGF23-pretreated (9,000 pg/ml) aortic rings, we found reductions in NO levels. We also investigated an animal model of CKD (Col4a3(-/-) mice) that displays highly elevated serum FGF23 levels and found they had impaired endothelium-dependent vascular relaxation and reduced nitrate production compared with age-matched wild types. To elucidate a mechanism for the FGF23-induced impairment, we measured superoxide levels in endothelial cells and aortic rings and found that they were increased following FGF23 treatment. Crucially, treatment with the superoxide scavenger tiron reduced superoxide levels and also restored aortic relaxation to ACh. Therefore, our data suggest that FGF23 increases superoxide, inhibits NO bioavailability, and causes endothelial dysfunction in mouse aorta. Together, these data provide evidence that high levels of FGF23 contribute to cardiovascular dysfunction.
authors: Muscle Biology Group, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri; and.
authors: Neerupma
authors: N
authors: Silswal
authors: Muscle Biology Group, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri; and.
authors: Chad D
authors: CD
authors: Touchberry
authors: Muscle Biology Group, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri; and.
authors: Dorothy R
authors: DR
authors: Daniel
authors: Muscle Biology Group, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri; and.
authors: Darla L
authors: DL
authors: McCarthy
authors: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors: Shiqin
authors: S
authors: Zhang
authors: Muscle Biology Group, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri; and.
authors: Jon
authors: J
authors: Andresen
authors: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors: Jason R
authors: JR
authors: Stubbs
authors: Muscle Biology Group, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri; and wackerm@umkc.edu.
authors: Michael J
authors: MJ
authors: Wacker
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics; D004730:Endothelium, Vascular / Q000502:physiology*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000502:physiology*; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000235:genetics*
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; C000717428:Fgf23 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; C057112:type IV collagen alpha3 chain; D013481:Superoxides; D009569:Nitric Oxide; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: and cardiovascular disease; chronic kidney disease; fibroblast growth factor 23; nitric oxide; superoxide