biostudies-literatureZiogas ANIDCR NIH HHSDeutsche ForschungsgemeinschaftNational Institutes of Healthe21425https://www.ebi.ac.uk/biostudies/studies/S-EPMC7909462biostudies-literatureUnknown35(3)Histamine-induced vascular leakage is a core process of allergic pathologies, including anaphylaxis. Here, we show that glycolysis is integral to histamine-induced endothelial barrier disruption and hyperpermeability. Histamine rapidly enhanced glycolysis in endothelial cells via a pathway that involved histamine receptor 1 and phospholipase C beta signaling. Consistently, partial inhibition of glycolysis with 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) prevented histamine-induced hyperpermeability in human microvascular endothelial cells, by abolishing the histamine-induced actomyosin contraction, focal adherens junction formation, and endothelial barrier disruption. Pharmacologic blockade of glycolysis with 3PO in mice reduced histamine-induced vascular hyperpermeability, prevented vascular leakage in passive cutaneous anaphylaxis and protected from systemic anaphylaxis. In conclusion, we elucidated the role of glycolysis in histamine-induced disruption of endothelial barrier integrity. Our data thereby point to endothelial glycolysis as a novel therapeutic target for human pathologies related to excessive vascular leakage, such as systemic anaphylaxis.FASEB journal : official publication of the Federation of American Societies for Experimental BiologyGlycolysis is integral to histamine-induced endothelial hyperpermeability.PMC7909462R37 DE026152DE026152TR‐SFB 127Witt AGrossklaus SZiogas ALim JHSajib MSHagag ESprott DMikelis CMMirtschink PGrinenko TChavakis TGerlach MHajishengallis GAlves TCDas AAndroulaki NNoll TfalseGlycolysis is integral to histamine-induced endothelial hyperpermeability.Histamine-induced vascular leakage is a core process of allergic pathologies, including anaphylaxis. Here, we show that glycolysis is integral to histamine-induced endothelial barrier disruption and hyperpermeability. Histamine rapidly enhanced glycolysis in endothelial cells via a pathway that involved histamine receptor 1 and phospholipase C beta signaling. Consistently, partial inhibition of glycolysis with 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) prevented histamine-induced hyperpermeability in human microvascular endothelial cells, by abolishing the histamine-induced actomyosin contraction, focal adherens junction formation, and endothelial barrier disruption. Pharmacologic blockade of glycolysis with 3PO in mice reduced histamine-induced vascular hyperpermeability, prevented vascular leakage in passive cutaneous anaphylaxis and protected from systemic anaphylaxis. In conclusion, we elucidated the role of glycolysis in histamine-induced disruption of endothelial barrier integrity. Our data thereby point to endothelial glycolysis as a novel therapeutic target for human pathologies related to excessive vascular leakage, such as systemic anaphylaxis.2021-01-01T00:00:00Z2021 Mar2026-06-01T02:09:23.387Z2025-04-04T19:54:06.168ZS-EPMC79094623356644310.1096/fj.202001634R