Figure 4.

Potential mechanisms involving uremic toxins and reactive oxygen species (ROS) in vascular calcification. Uremic toxins: Increased parathyroid hormone (PTH), phosphorus (Pi) and phosphate (PO₄⁻³), calcium, calcium × phosphorus product, vitamin D₃, and ROS significantly contribute to vascular smooth muscle cell (VSMC) and/or pericyte (Pc) differentiation into an osteoblast-like phenotype. Phosphate absorption into these cells is facilitated by the sodium phosphate cotransporter (Pit-1) resulting in an osteogenic switch due to activation of transcription factors: osteoblast-specific cis-acting element (Osf2)—core binding factor alpha1 (Cbfa-1/Runx2). Osteocalcin, osteonectin, bone morphogenic protein-2alpha and alkaline phosphatase (ALP) are inducers of calcification. In contrast, the systemic and local inhibitors of calcification fetuin-A—alpha2-Heremans-Schmid glycoprotein (AHSG) and matrix Gla protein (MGP) are decreased in uremia and calciphylaxis. Further, ROS and inflammatory cytokine surges may contribute to decreased hepatic synthesis of fetuin-A (insert a). Uremic toxins—ROS promote uncoupling of endothelial nitric oxide synthase (eNOS) enzyme via the oxidation of the requisite tetrahydrobiopterin (BH₄) cofactor and results in the endothelium becoming a net producer of superoxide—ROS (insert b). Additionally, decreased bioavailable eNO due to eNOS enzyme uncoupling promotes a proinflammatory, proconstrictive, prothrombotic vascular endothelium. ROS are also capable of promoting VSMC apoptosis in the arterial vascular wall (AVW) and when this occurs the matrix vesicles and apoptotic bodies serve as nucleating sites for further calcium deposition in the extracellular matrix of the arteriole media (inserts b–e) (Fig. 1).