The soluble epoxide hydrolase (sEH) is the most important arachidonic acid epoxide-metabolising enzyme and its deletion and/or inhibition have been linked with altered cardiovascular homeostasis and anti-inflammatory effects. Epoxyeicosatrienoic acids (EETs) are epoxides of arachidonic acid and substrates of the sEH that are known to promote angiogenesis. Therefore, this study was aimed at determining whether the angiogenic effects of the EETs could be demonstrated in sEH-/- mice. Moreover, we focussed on the role of the recruitment of bone marrow derived progenitor cells which are known to support vasculogenesis. In contrast to the angiogenic effect of 11,12-EET-impregnated Matrigel plugs in wild-type animals, sEH-/- mice showed a delayed recovery from hindlimb ischemia versus wild-type mice. Retarded revascularisation was also demonstrated in wild-type mice following sub-lethal irradiation and bone marrow transplantation with cells from sEH-/- mice. A similar phenomenon was also observed in SDF- impregnated Matrigel plugs implanted into sEH-/- mice treated with G-CSF. Direct measurements of G- CSF mobilized endothelial progenitor cells derived from spleen and hematopoietic progenitor cells isolated from peripheral blood (CFU-C and CFU-S12 assay) also revealed that the loss of the sEH was associated with reduced progenitor cell mobilization. EET levels were elevated in the bone marrow of sEH-/- mice but were not the most prominent sEH substrate. A lipid screen revealed that 19,20-epoxydocosapentaenoic (19,20-EpDPE) acid was the most abundant epoxide and that levels of this fatty acid increased exclusively in the bone marrow from sEH-/- mice. Taken together these data indicate that sEH is required for neovascularization after ischemia and the G- CSF-induced mobilization of hematopoietic progenitor cells. The accumulation of 19,20-EpDPE acid seems to prevent mobilization thus influencing angiogenesis and revascularization in the adult mouse in an EET-independent manner.