FGF23 blockade induces maladaptive vascular remodelling, reducing pathologically increased arterial stiffness and blood pressure
Nephrology Dialysis Transplantation
Abstract
BACKGROUND AND HYPOTHESIS: Elevated circulating levels of fibroblast growth factor 23 (FGF23) are linked to arterial stiffness and cardiovascular risk, and blocking FGF23 has been proposed as a therapeutic strategy. However, whether FGF23 inhibition is beneficial or detrimental for vascular function remains unknown. METHODS: We investigated the vascular consequences of blocking FGF23 in spontaneously hypertensive rats (SHR) treated for 14 days with a neutralizing antibody. Arterial stiffness, blood pressure, and extracellular matrix proteins involved in vascular remodelling were evaluated. In addition, Fibrillin-1, Fibronectin, and FGF23 were also analysed in renal arteries from nephrectomized patients. RESULTS: FGF23 blockade significantly reduced blood pressure and arterial stiffness in SHR rats and pulse wave velocity values fell below those of WKY controls, indicating abnormally low stiffness and excessive vascular relaxation. This was accompanied by a marked reduction in vasoactive compounds such as endothelin-1, adrenomedullin, and epinephrine, together with a compensatory rise in angiotensin II, III, and IV. Structural and ultrastructural analyses revealed aortic dilation, elastic fibres fragmentation, reduced collagen content, and abnormal vascular smooth muscle cell (VSMC) morphology. At the molecular level, FGF23 blockade decreased Fibrillin-1, Fibulin-5, and Fibronectin expression while increasing Fibulin-4, pointing to a maladaptive extracellular matrix remodelling. In addition, FGF23 neutralization reduced calcium influx in VSMC from SHR and decreased ORAI1 expression suggesting impaired vasomotor control. Human renal arteries from nephrectomized patients with elevated FGF23 also showed increased Fibrillin-1 and Fibronectin expression, correlating with higher pulse pressure. CONCLUSIONS: FGF23 blockade was associated with excessive arterial softening, hypotension, and structural vascular alterations in SHR rats. These findings support a role for FGF23 in vascular remodelling and blood pressure regulation under the experimental conditions used in this study but should not be directly extrapolated to clinically used anti-FGF23 therapies.
Authors 20
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Instituto Maimónides de Investigación Biomédica de Córdoba · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), RD24/0004/0004 , Madrid ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), RD24/0004/0004 , Madrid ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · Hospital Universitario Reina Sofía · University of Córdoba
Affiliation as printed
University of Cordoba, IMIBIC Department of Urology, Universitary Hospital Reina Sofía, , Córdoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · Hospital Universitario Reina Sofía · University of Córdoba
Affiliation as printed
University of Cordoba, IMIBIC Department of Urology, Universitary Hospital Reina Sofía, , Córdoba ,
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Affiliation as printed
Institute for Molecular Cardiovascular Research IMCAR, RWTH Aachen University , Aachen ,
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Affiliation as printed
COST Action CA21165 - Personalized medicine in chronic kidney disease: improved outcome based on Big Data (PerMediK)
European Uremic Toxins Group (EUTOx)
Institute for Molecular Cardiovascular Research IMCAR, RWTH Aachen University , Aachen ,
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Maastricht University · RWTH Aachen University
Affiliation as printed
CARIM, Cardiovascular Research Institute Maastricht, Maastricht University Department of Pathology, , Maastricht ,
COST Action CA21165 - Personalized medicine in chronic kidney disease: improved outcome based on Big Data (PerMediK)
European Uremic Toxins Group (EUTOx)
Institute for Molecular Cardiovascular Research IMCAR, RWTH Aachen University , Aachen ,
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Consejo Superior de Investigaciones Científicas · Universidad Loyola Andalucía · Instituto de Biomedicina de Sevilla · Hospital Universitario Virgen del Rocío · Universidad de Sevilla
Affiliation as printed
Faculty of Health Sciences, Universidad Loyola Andalucía , Seville ,
Instituto de Biomedicina de Sevilla y Departamento de Fisiología Médica y Biofísica, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla , Seville ,
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Hospital Universitario Reina Sofía · University of Córdoba
Affiliation as printed
University of Cordoba/Pathology Unit, Hospital Universitario Reina Sofía Departament of Morphological and Sociosanitary Sciences, Pathology Unit, Faculty of Medicine and Nurse, , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), RD24/0004/0004 , Madrid ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · Hospital Universitario Reina Sofía · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
Nephrology Service, Reina Sofia University Hospital , Cordoba ,
Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), RD24/0004/0004 , Madrid ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · Hospital Universitario Reina Sofía · University of Córdoba
Affiliation as printed
COST Action CA21165 - Personalized medicine in chronic kidney disease: improved outcome based on Big Data (PerMediK)
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
European Uremic Toxins Group (EUTOx)
Nephrology Service, Reina Sofia University Hospital , Cordoba ,
Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), RD24/0004/0004 , Madrid ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · Hospital Universitario Reina Sofía · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
Nephrology Service, Reina Sofia University Hospital , Cordoba ,
Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), RD24/0004/0004 , Madrid ,
University of Cordoba , Cordoba ,
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Instituto Maimónides de Investigación Biomédica de Córdoba · Hospital Universitario Reina Sofía · University of Córdoba
Affiliation as printed
Calcium Metabolism and Vascular Calcification Unit, Maimonides Institute for Biomedical Research (IMIBIC) , Cordoba ,
Nephrology Service, Reina Sofia University Hospital , Cordoba ,
Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), RD24/0004/0004 , Madrid ,
University of Cordoba , Cordoba ,
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