Long Non-coding RNA TYKRIL Regulates Pericyte Survival in the Cardiovascular and Central Nervous System in vivo in a p53 Dependent Manner

Background: Vessel maturation is dependent on platelet derived growth factor (PDGF), which signals via tyrosine kinase receptors and facilitates recruitment of pericytes. Long noncoding RNAs (lncRNAs) regulate endothelial and smooth muscle cell properties, but their role in pericyte function is unclear. Hypothesis: Here we assessed the hypothesis that lncRNA TYKRIL (Tyrosin kinase receptor inducing lncRNA) regulates pericyte survival. Results and Discussion: Using RNA sequencing, we identify the hypoxia induced lncRNA TYKRIL as a species conserved lncRNA which regulates pericyte survival in vitro and in vivo. Using RNA immunoprecipitation (RIP) we demonstrate that TYKRIL binds to p53 (TYKRIL enrichment fold change (FC) 2.7±0.27 vs Ctrl. P TYKRIL loss fostered p53-p300 interaction in proximity ligation assays (3.57±0.5 FC vs Ctrl., P Targeting the murine TYKRIL orthologue in the CNS in vivo by LNA GapmeRs resulted in pericyte loss in the cerebral cortex (0.4±0.09 FC vs. Ctrl, P Conclusion: Here, we identify the lncRNA TYKRIL as a p53 decoy molecule that represses p53 activation, thereby regulating pericyte survival in vitro and in vivo. Our results identify TYKRIL as a regulator of pericyte function, which may enable to develop novel concepts for pro- or anti-angiogenic therapies in cardiovascular disease and malignancy.