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July 15th, 2025
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University Hospital of the RWTH Aachen
systems biology
biorxiv

The role of Platelet-derived growth factor (PDGF) in uremic vascular calcification.

Yesilyurt Ozturk, B.Open in Google Scholar•Zhang, L.Open in Google Scholar•von Stillfried, S.Open in Google Scholar•Klinkhammer, B. M.Open in Google Scholar•Mollmann, J.Open in Google Scholar•Droste, P.Open in Google Scholar•Buhl, E. M.Open in Google Scholar•Hohl, M.Open in Google Scholar•Noels, H.Open in Google Scholar•Jankowski, V.Open in Google Scholaret al.

Vascular calcification is common in chronic kidney disease (CKD), contributing to increased cardiovascular morbidity and mortality. One of the proposed mechanisms of 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-{beta}, were shown to modulate the VSMC phenotype. However, their role in uremic vascular calcification remained unclear. We adapted an ex vivo calcification model using murine aortas to simulate uremic conditions. Compared to control conditions, incubation with hemodialysate from CKD patients or using aortas from CKD animals both resulted in significantly increased PDGFR-{beta} phosphorylation and vascular calcification. Inhibition of PDGF signaling using soluble PDGFR-{beta} or the small molecule tyrosine kinase inhibitor imatinib significantly reduced uremic calcification and enhanced vascular elasticity. Next, we generated transgenic mice with a VSMC-specific, inducible expression of constitutively active PDGFR-{beta}. The aortas of these mice exhibited significantly increased vascular calcification ex vivo, which was further aggravated by uremic conditions. We established an in vivo model of accelerated vascular calcification and CKD in the transgenic mice, showing significantly aggravated vascular calcification and phenotypic switching of VSMCs compared to non-transgenic littermates. Finally, increased expression of phosphorylated PDGFR-{beta} and a VSMC phenotypic switching were detected in human arteries from patients with CKD compared to those without CKD. In conclusion, PDGFR-{beta} contributes to CKD-associated vascular calcification, representing a potential novel therapeutic target.

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