Stimulator of Interferon Genes (STING) regulates Re‐endothelialization Following Vascular Injury.

R1616 --> Percutaneous coronary interventions (PCI) are commonly used to improve blood flow in Peripheral Artery Disease. Complications of PCI are delayed re‐endothelialization and endothelial cell (EC) dysfunction leading to adverse clinical outcomes. Stimulator of Interferon Genes (STING), canonically activated downstream of the cGAS enzyme, is a signaling hub molecule modulating immune responses triggered by self‐derived and/or foreign DNA. We hypothesized that EC‐intrinsic STING regulates re‐endothelialization in response to vascular injury. We modeled PCI in WT, STING‐/‐, and in a newly generated inducible vascular EC‐ specific mouse (VECad5Cre‐ERT2STINGfl/fl mice: EC‐STING‐/‐) using the wire induced carotid injury model. We used Evans Blue Dye injection post injury to identify the areas denuded of EC and quantified the % of non‐blue (re‐endothelialized) area. We found that WT mice had complete re‐endothelialization five days post injury (95.16 ± 2.77 %). In contrast, injured carotid arteries in STING‐/‐ mice exhibited a decrease in re‐endothelialization at the same timepoint (43.57 ± 9.79%). Moreover, EC‐STING‐/‐ mice recapitulated the delayed re‐endothelialization (10.45 ± 1.56% in Tamoxifen treated mice to induce excision of STING in EC, compared to 40 ± 1.28% observed in vehicle treated VECad5Cre‐ERT2STINGfl/fl control mice 5 days post scratch) in the injured arteries, supporting a role of EC STING in re‐endothelialization post injury. To further investigate this EC‐specific effect of STING mechanistically in vitro, we performed scratch assays on WT and STING mouse heart EC (MHEC) monolayers, as well as on human EC monolayers lacking STING after CRISPR knock down and imaged wound healing in real time by IncuCyte. WT MHEC and HUVEC completely covered the scratch area within 24 hours, and 4 hours, respectively, whereas both EC lacking STING were delayed healing the scratch. Additionally, we found that the healing response was independent of cGAS, since cGAS KD HUVEC had similar post‐ scratch recovery time as control HUVEC. Ongoing experiments investigate the mechanisms involved in this novel STING dependent, cGAS‐independent pathway of EC response to injury, as well as the consequences of EC‐STING in adverse chronic vascular remodeling. [ABSTRACT FROM AUTHOR]