PF4/CXCR3 signaling contributes to the regulation of endothelial cells on smooth muscle cells in CKD vascular calcification.

Abstract

Vascular calcification is a common complication of chronic kidney disease (CKD) that increases the risks of cardiovascular morbidity and mortality. However, current therapeutic strategies are unable to effectively cure vascular calcification. To elucidate the effect of endothelial cells (ECs) on vascular smooth muscle cells (VSMCs) in CKD vascular calcification, this study observed an increased platelet factor 4 (PF4) level in ECs by a rat CKD vascular calcification model established by 5/6 nephrectomy with a high‑phosphorus diet. The role of PF4 was further investigated using a Vitamin D3-induced mouse vascular calcification model and a co-culture cell calcification model of ECs and VSMCs. We observed an enhanced colocalization of PF4 and the endothelial marker CD31 in aortic tissues of rats with CKD vascular calcification. PF4 overexpression exacerbated vascular calcification in mice. PF4 knockdown in ECs inhibited osteogenic transdifferentiation and calcium deposition of VSMCs. Knockdown of PF4 receptor C-X-C chemokine receptor 3 (CXCR3) alleviated calcification of VSMCs, and CXCR3 antagonist AMG487 attenuated vascular calcification involving PF4 in the regulation of ECs on VSMCs. The phosphorylation of PERK was increased in calcification medium-induced VSMCs. Immunoprecipitation showed an interaction between CXCR3 and PERK in VSMCs. Both CXCR3 knockdown and AMG487 could attenuate calcification of VSMCs involving the PERK-NRF2 pathway. Consequently, this study elucidated the critical role of PF4/CXCR3 signaling in the regulation of ECs on VSMCs in CKD vascular calcification involving the PERK-NRF2 pathway. PF4/CXCR3 signaling may represent a potential target for CKD vascular calcification.