FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability
FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability
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DOI：
10.1152/ajpendo.00264.2014
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发表时间：
2014-09-01
影响因子：
5.1
通讯作者：
Wacker, Michael J.
中科院分区：
文献类型：
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作者：
Silswal, Neerupma;Touchberry, Chad D.;Wacker, Michael J.
成纤维细胞生长因子23（FGF 23）主要由骨细胞分泌并调节磷酸盐和维生素D代谢。FGF 23水平升高在临床上与慢性肾病（CKD）患者的内皮功能障碍和动脉僵硬相关;然而，FGF 23对内皮功能的直接影响尚不清楚。我们假设FGF 23通过阻碍一氧化氮（NO）的生物利用度直接损害内皮血管舒张。我们检测了所有四种FGF受体亚型（Fgfr 1 -4）在雄性小鼠睾丸中的表达。外源性FGF 23（90- 9，000 pg/ml）不诱导主动脉环收缩，并且不松弛用PGF（2 α）预收缩的环。然而，与FGF 23（9，000 pg/ml）预孵育导致对预收缩主动脉环中乙酰胆碱（ACh）引起的内皮依赖性舒张的类似36%抑制，这被FGFR拮抗剂PD 166866（50 nM）阻止。此外，在FGF 23预处理（9，000 pg/ml）的主动脉环中，我们发现NO水平降低。我们还研究了一种CKD动物模型（Col 4a 3（-/-）小鼠），该模型显示血清FGF 23水平高度升高，并发现与年龄匹配的野生型相比，它们的内皮依赖性血管舒张受损，硝酸盐产生减少。为了阐明FGF 23诱导损伤的机制，我们测量了内皮细胞和主动脉环中的超氧化物水平，发现它们在FGF 23治疗后增加。至关重要的是，用超氧化物清除剂Tiron治疗降低了超氧化物水平，也恢复了ACh对主动脉的舒张。因此，我们的数据表明，FGF 23增加超氧化物，抑制NO的生物利用度，并导致小鼠主动脉内皮功能障碍。总之，这些数据提供了证据表明高水平的FGF 23有助于心血管功能障碍。
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 PGF(2 alpha). However, preincubation with FGF23 (9,000 pg/ml) caused a similar to 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.