Ziegler, TilmanTilmanZieglerHorstkotte, JanJanHorstkotteSchwab, ClaudiaClaudiaSchwabPfetsch, VanessaVanessaPfetschWeinmann, KarolinaKarolinaWeinmannDietzel, SteffenSteffenDietzelRohwedder, InaInaRohwedderHinkel, RabeaRabeaHinkelGross, LisaLisaGrossLee, SeungminSeungminLeeHu, JunhaoJunhaoHuSoehnlein, OliverOliverSoehnleinFranz, Wolfgang M.Wolfgang M.FranzSperandio, MarkusMarkusSperandioPohl, UlrichUlrichPohlThomas, MarkusMarkusThomasWeber, ChristianChristianWeberAugustin, Hellmut G.Hellmut G.AugustinFässler, ReinhardReinhardFässlerDeutsch, UrbanUrbanDeutschKupatt, ChristianChristianKupatt2024-10-152024-10-152013-08-01https://boris-portal.unibe.ch/handle/20.500.12422/120070Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.en600 - Technology::610 - Medicine & healtharticle10.7892/boris.497892386362910.1172/JCI66549