Dysregulated Klotho and FGF23 signalling aggravates vascular remodelling in age-related pulmonary hypertension

AIMS: Pulmonary arterial hypertension (PAH) is a chronic condition of elevated pulmonary arterial pressure caused by vascular remodelling due to increased proliferation of pulmonary arterial smooth muscle cells (PASMC). Initially described as a disease primarily affecting young women, it now increasingly affects the elderly. Age-related pathomechanisms of PAH remain, however, unclear. In a translational approach combining preclinical disease models and analyses of human cohorts, we probed for a role of the anti-ageing protein Klotho, which acts as a co-receptor for fibroblast growth factor 23 (FGF23) in the pathogenesis of PAH. METHODS AND RESULTS: Mice aged 114-117 weeks showed moderate spontaneous PAH with right ventricular (RV) hypertrophy and dysfunction relative to young mice aged < 40 weeks. This effect was further pronounced upon hypoxic exposure (10% O2) for 14 days. Histological sections showed pulmonary vascular wall thickening of small pulmonary arterioles. Similar findings were obtained in mice with a partial Klotho deficiency (kl/+) that developed RV systolic pressures (RVSP) of 72.58 ± 3.3 mmHg within two weeks of hypoxia. Aged mice and kl/+ mice had elevated plasma levels of FGF23, further amplified by hypoxic exposure. ELISA-based measurements in serum of patients from a cross-sectional study with PAH aged 60 years or older confirmed an increase in circulatory FGF23. Immunohistochemistry staining of lung tissue showed increased proliferative activity of PASMC in kl/+ mice, and recombinant FGF23 elevated proliferative activity of PASMC in vitro. The hyperproliferative response to FGF23 was prevented by siRNA-mediated knockdown of fibroblast growth factor receptor 1 in PASMC. In kl/+ mice, FGF23 neutralisation using an anti-FGF23 antibody reduced RVSP, improved RV dysfunction and RV hypertrophy and prevented pulmonary vascular remodelling. CONCLUSION: Our findings identify the accumulation of FGF23 as novel mechanism of pulmonary vascular remodeling in PAH. Targeting dysregulated Klotho/FGF23 signalling may present a promising therapeutic strategy in elderly patients.