Adenylosuccinate acts as a novel pro-angiogenic factor

We recently demonstrated a dramatic 77-fold increase in brain adenylosuccinate (AdSucc) concentration during ischemia, reaching ~0.56 mM levels. Previously, the role of AdSucc induction under decreased energy charge was attributed to the activation of purine nucleotide (PNC) and the tricarboxylic acid cycle (TCA). However, careful analysis of metabolomic alterations in the ischemic brain under decreased energy charge did not confirm this role. To begin addressing the additional biological significance of the increased AdSucc under low-energy conditions associated with ischemia, we tested its angiogenic properties. Using a mouse in vivo angiogenesis assay, we discovered that AdSucc, but not its metabolites such as adenosine or AMP accumulated during the assay, promotes angiogenesis in vivo at concentrations found in ischemic tissues. Further, using in vitro angiogenesis assay with human umbilical vein endothelial cells (HUVEC), we demonstrated that AdSucc promotes the formation of capillary-like structures (tubes) on extracellular matrix support. We also report, for the first time, that AdSucc increases cAMP levels, supporting its signaling role, which may be linked to pro-angiogenic mechanisms. Together, our data indicate a novel mechanism of angiogenesis regulation, in which AdSucc may serve as a new signaling molecule under low-energy conditions. Further studies are required to confirm the role of endogenously produced AdSucc in tissue angiogenesis as an adaptation mechanism to low-energy conditions and repair after injury.