Elastin calcification during the initial stage of vascular calcification in kl/kl mice is suppressed by the calcimimetic upacicalcet

Abstract

Abstract We performed ultrastructural analyses of the aortae of klotho -deficient ( kl/kl ) mice to characterize the early stages of medial calcification and to evaluate the inhibitory effects of the calcimimetic upacicalcet. In the aorta of kl/kl mice, calcified materials were localized to the superficial layers of fragmented elastic laminae and were observed as minute, nodule-like elastin aggregates containing calcium phosphate deposits. Although the gene expression of elastin-degrading enzymes and osteogenic markers was increased in kl/kl mice, these elastin aggregates were ultrastructurally distinct from conventional matrix vesicles or osteoblast-derived calcifying nodules observed in bone. In contrast, highly calcified regions of the kl/kl aorta contained bone-like tissue composed of cells exhibiting osteoblastic, osteocytic, and osteoclastic phenotypes. Administration of upacicalcet attenuated elastin fragmentation and significantly reduced medial calcification in the aorta. In addition to lowering serum calcium and parathyroid hormone levels, upacicalcet reduced serum phosphate concentrations and suppressed the expression of elastin-degrading enzymes and osteogenic markers. Collectively, these findings demonstrate that vascular calcification in kl/kl mice involves a complex pathological process comprising passive calcific deposition on degraded elastin and biologically regulated calcification and ossification mediated by osteoblast-like cells and that upacicalcet mitigates disease progression by preserving the structural integrity of aortic elastic laminae.