Abstract 341: The P2Y2 Nucleotide Receptor Regulates Vascular Calcification

Abstract

Objective: Vascular calcification is widespread in individuals with atherosclerosis, and is associated with inflammatory changes and expression of osteoblast-like cell phenotypes. Recent studies identified extracellular nucleotides and P2Y receptor cascade as important regulators of bone remodeling. We investigated the potential role of the P2Y2 receptor (P2Y2R) in vascular calcification. Methods and Results: P2Y2R-null mice were crossed with ApoE-null mice to generate P2Y2R/ApoE double knock-out mice. When fed a standard mouse chow diet for 16 weeks, P2Y2R–/–/ApoE–/– mice showed significant higher intimal calcification as compared to their APOE–/– counterparts. Smooth muscle cells (SMCs) isolated from aortas of P2Y2R +/+ and P2Y2R -/- mice were identical in morphology and stained positively for SM lineage proteins including, desmin, smooth muscle and SM22alpha. When cultured in medium containing high concentrations of inorganic phosphate, an inducer of vascular calcification, a remarkably higher calcification was observed in P2Y2R -/- SMCs compared to P2Y2R +/+ SMCs. Furthermore, retroviral transduction of mouse P2Y2RcDNA into P2Y2R -/- SMCs rescued the calcification phenotype of the cells. Conclusion: These results demonstrate that inactivation of the P2Y2R gene regulates vascular calcification both in vivo and in vitro, suggesting that drugs targeting this receptor could prevent complications associated with vascular calcification