Abstract

Endothelial cells (ECs) express fibroblast growth factor (FGF) receptors and are metabolically active after treatment with FGF-23. It is not known if this effect is α-Klotho independent or mediated by humoral or endogenous endothelial α-Klotho. In the present study, we aimed to characterize EC α-Klotho expression within the human vascular tree and to investigate the potential role of α-Klotho in determining FGF-23 mediated EC regulation. Human tissue and ECs from various organs were used for immunohistochemistry and Western blot. Primary cultures of human aortic endothelial cells (HAECs) and human brain microvascular endothelial cells (HBMECs) were used to generate in vitro cell models. We found endogenous α-Klotho expression in ECs from various organs except in microvascular ECs from human brain. Furthermore, FGF-23 stimulated endothelial nitric oxide synthase (eNOS) expression, nitric oxide (NO) production, and cell proliferation in HAECs. Interestingly, these effects were not observed in our HBMEC model in vitro. High phosphate treatment and endothelial α-Klotho knockdown mitigated FGF-23 mediated eNOS induction, NO production, and cell proliferation in HAECs. Rescue treatment with soluble α-Klotho did not reverse endothelial FGF-23 resistance caused by reduced or absent α-Klotho expression in HAECs. These novel observations provide evidence for differential α-Klotho functional expression in the human endothelium and its presence may play a role in determining the response to FGF-23 in the vascular tree. α-Klotho was not detected in cerebral microvascular ECs and its absence may render these cells nonresponsive to FGF-23.

Highlights

  • Normal vascular function is critically dependent on physiological endothelial cell (EC) responses to altered tissue nutrient demand and an appropriate stress response

  • Our results showed that fibroblast growth factor (FGF)-23 stimulated proliferation of human aortic endothelial cells (HAECs), in vitro only when cells were treated with fibroblast growth factor 23 (FGF-23) concentrations > 50 ng/ml

  • We investigated whether FGF-23 could play a role in regulating endothelial nitric oxide (NO) production in human ECs

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Summary

Introduction

Normal vascular function is critically dependent on physiological endothelial cell (EC) responses to altered tissue nutrient demand and an appropriate stress response. The endothelium generates many factors that regulate vascular tone, adhesion of circulating blood cells, smooth muscle proliferation, and inflammation; as such, EC dysfunction has emerged as a relevant risk marker for cardiovascular events in the general population, older individuals [1], patients with diabetes [2], or renal impairment [3]. The phosphate and vitamin D regulating hormone fibroblast growth factor 23 (FGF-23) has been implicated in cardiovascular risk of patients with normal and impaired renal function [4, 5]. We have recently shown that transmembrane cell surface α-Klotho is expressed in numerous human tissues beyond the kidney and parathyroid gland, including the smooth muscle cell layer of the artery wall [9, 10]

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