The role of platelet-derived growth factor in uremic vascular calcification.

INTRODUCTION: Vascular calcification is common in chronic kidney disease (CKD), contributing to increased cardiovascular morbidity and mortality. A proposed mechanism for driving vascular calcification is a phenotypic switch of vascular smooth muscle cells (VSMCs). The platelet derived growth factors (PDGFs) and their receptors (PDGFRs), particularly PDGFR-β, were shown to modulate the VSMC phenotype. However, their role in uremic vascular calcification remained unclear.

METHODS: To study this, we adapted an ex vivo calcification model using murine aortas to simulate uremic conditions. Next, we generated transgenic mice with a VSMC-specific, inducible expression of constitutively active PDGFR-β and established an in vivo model of accelerated vascular calcification and CKD in the transgenic mice.

RESULTS: Compared to control conditions, incubation of mouse aortas with dialysis fluid from uremic patients on hemodialysis therapy or examination of aortas from CKD animals both revealed increased PDGFR-β phosphorylation and vascular calcification. Inhibition of PDGF signaling using soluble PDGFR-β or the small molecule tyrosine kinase inhibitor imatinib reduced uremic calcification and enhanced vascular elasticity. Next, we generated transgenic mice with a VSMC-specific, inducible expression of constitutively active PDGFR-β. The aortas of these mice exhibited increased calcification ex vivo, which was further aggravated by uremic conditions, attesting a phenotypic switch of VSMCs compared to non-transgenic littermates. Finally, increased expression of phosphorylated PDGFR-β and a VSMC phenotypic switch were detected in arteries from patients with CKD stage 5 compared to age- and sex-matched patients without CKD and with non-calcified arteries.

CONCLUSIONS: PDGFR-β contributes to CKD-associated vascular calcification, representing a potential novel therapeutic target.