FGF23 blockade induces maladaptive vascular remodelling, reducing pathologically increased arterial stiffness and blood pressure

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.