Ischemia/ reperfusion-induced and sepsis-induced endothelial dysfunction is initiated by increased amounts of reactive oxygen species. 1. Ascorbate reduces the production of superoxide (O2
–), hydrogen peroxide and peroxynitrite (OONO–) by inhibiting the Jak2/Stat1/IRF1 signaling pathway, which leads to subunit p47phox expression of nicotinamide adenine dinucleotide phosphate oxidase (NADPH-ox) and thus to O2
– formation. 2. Ascorbate protects against oxidative stress induced pathological vasoconstriction and loss of endothelial barrier by inhibiting tetrahydrobiopterin (BH4) oxidation, the cofactor of endothelial nitric oxide synthase (eNOS), thereby preventing endothelial nitric oxide (eNO) depletion and eNOS uncoupling. 3. Ascorbate inhibits inducible nitric oxide synthase (iNOS) mRNA and iNOS expression, preventing abundant production of nitric oxide (NO) that generates OONO– in the presence of O2
–. 4. Ascorbate protects against vascular leakage by inhibiting protein phosphatase 2A (PP2A) activation, which dephosphorylates occludin. Phosphorylated occludin is crucial for maintenance of tight junctions. 5. Ascorbate inhibits myocardial apoptosis by preventing Bax activation, which decreases the ability of BCl-2 to inhibit cytochrome-C release from the mitochondria into the cytoplasm and subsequent caspase-3 activation, which initiates apoptosis. The combination with vitamin E is synergistic. 6. Ascorbate inhibits microcirculatory flow impairment by inhibiting tumor necrosis factor-induced intracellular adhesion molecule (ICAM) expression, which triggers leukocyte stickiness and sludging. cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; I/R, ischemia/reperfusion; sGC, soluble guanylate cyclase.