Abstract
Vascular endothelial cells that cover the luminal surface of blood vessels control several vascular functions, in which heparan sulfate proteoglycans (HSPGs) are involved. Although the amount of HSPGs decreases in association with the progression of atherosclerosis, the mechanisms underlying the regulation of endothelial HPSG synthesis remain unclear. Adenine metabolites (ATP, ADP, and adenosine) are released from cytosol to extracellular space by extracellular-derived stimuli including inflammatory response, which bind to purinergic receptors and regulate cellular functions. In this study, we elucidate the influence of the adenine metabolites on the transcriptional regulation of endothelial HSPG synthesis and the purinergic receptors involved in the transcriptional regulation. The expression of endothelial perlecan mRNA was decreased by ATP, but not ADP and adenosine. The expression of syndecan-1 mRNA was decreased by not only ATP but also ADP and adenosine. The expression of syndecan-4 mRNA was first increased and then decreased by ATP, ADP, and adenosine. A2BR, P2X4R, P2X7R, P2Y1R, and P2Y2R were expressed in vascular endothelial cells. siRNA-mediated knockdown indicated that P2X4R and P2Y2R were involved in the transcriptional repression of perlecan by ATP; P2X4R and P2Y1R were involved in the transcriptional repression of syndecan-1 by ATP and ADP. Additionally, A2BR and P2X4R were involved in the early transcriptional induction of syndecan-4 by ATP and ADP, and P2Y2R in the subsequent suppression.
