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Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to various illnesses and fatal outcomes. The disease is multisystemic and can cause vascular endothelial injury. The Angiopoietin 1/Tie 2 pathway is important in endothelium quiescence and vessel stability. Angiopoietin 1 (Ang1) exerts its protective effect by activating Tie-2 receptors and subsequently the Phosphatidylinositol 3-kinase (PI3Kinase)/AKT pathway. It also inhibits NF-κB activity. Tie-1 regulates Ang-1 signalling with high levels of the receptor reducing Ang-1signalling. While there is evidence linking SARS-CoV-2 to endothelial dysfunction, no evidence exists of the impact the virus has on the Angiopoietin/Tie signalling axis.Aim To examine the impact the seasonal human coronavirus OC43 (HCOV-OC43) has on Tie receptor expression and consequently Angiopoietin-1 signaling in endothelial cells.Methods HCoV-OC43 (2008103v) was cultured in HCT-8 epithelial cells in RPMI-1640 with 5% FBS for 7 days before harvesting the virus stock. Multiplicity of infection (MOI) 1 was used to optimise primary Human Umbilical Vein Endothelial cell (HUVEC) infection with HCOV-OC43. The TCID 50 assay and Immunofluorescence staining were used to assess the infection rate. Cell lysates were obtained from HUVEC infected with or without OC43, treated with Angiopoietin 1 (200 ng/ml). Cell lysates from the treated cells were then subjected to Western blotting and probed for Tie receptors and Ang1-Tie2 downstream signalling molecules. Immunoprecipitation of cell lysates with Anti-Tie2 followed by Western blot with Anti-PY99 were performed to determine Ang1-induced Tie2 phosphorylation (pTie2). The levels of target proteins were compared between reactions by quantifying mean intensity of bands. Data values are expressed as mean and standard deviation. Shapiro Wilk test was used to assess the distribution of the data. An alpha value of p < 0.05 was set to indicate statistical significance.Results Cells were infected with OC43 (MOI-1), leading to a significant increase in N protein levels at 48 hours post-infection (p=0.0005). Viral infection altered Tie2/Tie1 ratio by reducing the expression of Tie1 after 24 and 48 hours (p=0.004, p=0.002; respectively). While Phospho-Tie2 showed an increase in activity, pAkt activation was significantly increased at 48 hours post-infection in the presence of Ang1 (p=0.01 vs Control-Ang1) with the activity of NF-κB being reduced (P=0.000095 vs Control-Ang1)Conclusion These results demonstrate that the OC43 virus is capable of directly infecting endothelial cells and that it increases the Tie2/Tie1 ratio through reducing Tie1 protein expression. In turn Ang1 induced pTie2 is elevated in virus infected cells and alters downstream signalling pathway by reducing NF-κB and increasing Akt activity, suggesting to prevent hyper-inflammation and preserving endothelial integrity.