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 PDGFRβ 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 PDGFRβ phosphorylation and vascular calcification. Inhibition of PDGF signaling using soluble PDGFR-β or the oral 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 PDGFRβ. 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.
Öztürk et al. (Mon,) studied this question.