32736 Characterizing calciphylaxis-like lesions in mice predisposed to vascular calcification

Abstract

Calciphylaxis is a rare yet fatal form of vascular calcification often associated with end-stage renal disease (uremic calciphylaxis) and nonuremic causes. Calciphylaxis is associated with medial arteriolar vascular calcification and results in ischemic subcutaneous necrosis. We hypothesized that tissue-nonspecific alkaline phosphatase (TNAP), which is known to cause osteoblastic transformation of vascular cells, can contribute to the calcification of small arterioles in the skin. Our study aimed to characterize a mouse model of nonuremic calciphylaxis secondary to alkaline phosphatase overexpression in the vasculature. Eleven wild-type (WT) and 11 TNAP mice were evaluated at 23-week-old age on a regular diet. Alizarin and hematoxylin and eosin (H&E) staining of trunk skin cryosections revealed calcium deposits in TNAP mice. As visualized by vascular contrast micro-CT, calcifications appeared primarily vascular in nature and localized to the dermis and subcutaneous adipose tissue. Noncontrast micro-CT (n = 4 per group) revealed that calcification was present in all TNAP mice compared with its complete absence in WT mice. The presence of vascular calcification in adipose-rich trunks of the TNAP mice is consistent with the pattern of lesion formation in human calciphylaxis patients. Our mice tissues are most reflective of the earliest histologic manifestations, which lack ulcerations or necrotic lesions, but may be characterized by gross skin changes with intact epithelium. Our findings suggest that increased alkaline phosphatase activity in the vasculature can contribute to the pathophysiology of nonuremic calciphylaxis.