The Pathogenic Roles of Local Vitamin D Metabolism Defect in Valve Inflammation and Calcification

This study identifies the valvular interstitial cell populations responsible for valvular calcification induced by hyperphosphatemia and likely aging, uncovers local vitamin D metabolism defect‐induced inflammation as a critical pathogenic factor of calcific aortic valve disease, and highlights active vitamin D and ERK inhibitor as potential preventive treatment for this disease. Abstract Calcific aortic valve disease (CAVD) is a highly prevalent disease that leads to heart failure. However, the pathogenesis of CAVD remains poorly understood, and the disease currently lacks medicinal treatment. In this study, utilizing a high‐phosphate‐diet‐induced valvular calcification model in conjunction with single‐cell profiling and genetic tracing, two subpopulations of Prrx1+Acta2− valve interstitial cells (VICs) are identified that underwent osteogenic differentiation. Mechanistically, elevated phosphate suppresses the expression of vitamin D metabolism genes primarily in VICs and response genes in immune cells, leading to local activation of CD8+ T cells, macrophages, and Prox1+ endothelial cells in the valve. It is further shown that inflammatory cytokines and phosphate ions synergistically induced VIC osteogenic differentiation via extracellular regulated protein kinases (ERK) signaling. Administration of active vitamin D but not the inactive form suppressed inflammation and mitigated valvular calcification. Moreover, the VIC subpopulations undergoing osteogenic differentiation, suppressed expression of vitamin D metabolism and response genes, and inflammation are also observed in valve samples from patients with CAVD. This study reveals the cellular and molecular basis for valvular calcification and identifies active vitamin D as a potential drug to prevent CAVD development. This study identifies the valvular interstitial cell populations responsible for valvular calcification induced by hyperphosphatemia and likely aging, uncovers local vitamin D metabolism defect-induced inflammation as a critical pathogenic factor of calcific aortic valve disease, and highlights active vitamin D and ERK inhibitor as potential preventive treatment for this disease. Abstract Calcific aortic valve disease (CAVD) is a highly prevalent disease that leads to heart failure. However, the pathogenesis of CAVD remains poorly understood, and the disease currently lacks medicinal treatment. In this study, utilizing a high-phosphate-diet-induced valvular calcification model in conjunction with single-cell profiling and genetic tracing, two subpopulations of Prrx1 + Acta2 − valve interstitial cells (VICs) are identified that underwent osteogenic differentiation. Mechanistically, elevated phosphate suppresses the expression of vitamin D metabolism genes primarily in VICs and response genes in immune cells, leading to local activation of CD8 + T cells, macrophages, and Prox1 + endothelial cells in the valve. It is further shown that inflammatory cytokines and phosphate ions synergistically induced VIC osteogenic differentiation via extracellular regulated protein kinases (ERK) signaling. Administration of active vitamin D but not the inactive form suppressed inflammation and mitigated valvular calcification. Moreover, the VIC subpopulations undergoing osteogenic differentiation, suppressed expression of vitamin D metabolism and response genes, and inflammation are also observed in valve samples from patients with CAVD. This study reveals the cellular and molecular basis for valvular calcification and identifies active vitamin D as a potential drug to prevent CAVD development. Advanced Science, Volume 12, Issue 48, December 29, 2025.