The　angiopoietin　(Ang)-Tie　axis,　critical　for　endothelial　cell　function　and　vascular　development,　is　a　promising　therapeutic　target　for　treating　vascular　disorders　and　inflammatory　conditions　like　sepsis.　This　study　aimed　to　enhance　the　binding　affinity　of　recombinant　Ang1　variants　to　the　Tie2　and　explore　their　therapeutic　potential.　Structural　insights　from　the　Ang1-Tie2　complex　enabled　the　identification　of　key　residues　within　the　Ang1　receptor　binding　domain　(RBD)　critical　for　Tie2　interaction.　Molecular　dynamics　simulations　revealed　that　Met436Arg　(M436R)　and　Ala451Asp　(A451D)　could　improve　Ang1＇s　Tie2　binding　affinity.　One　variant,　Ang1-RBDA451D,　demonstrated　a　100-fold　increase　compared　to　the　wild　type.　Cellular　assays　revealed　that　Ang1A451D　enhanced　Tie2　phosphorylation,　promoting　endothelial　cell　migration　and　tube　formation.　In　vivo,　this　variant　effectively　reduced　inflammatory　cytokines　and　attenuated　organ　damage　in　septic　mice.　These　findings　highlight　Ang1A451D　as　a　promising　therapeutic　candidate　for　vascular　diseases,　offering　notable　clinical　potential　for　mitigating　sepsis-related　vascular　dysfunction.　©　2025　The　Authors,　some　rights　reserved;　exclusive　licensee　American　Association　for　the　Advancement　of　Science.　No　claim　to　original　U.S.　Government　Works.　Distributed　under　a　Creative　Commons　Attribution　NonCommercial　License　4.0　(CC　BY-NC).