TY - JOUR
T1 - Soluble epoxide hydrolase regulates hematopoietic progenitor cell function via generation of fatty acid diols
AU - Frömel, Timo
AU - Jungblut, Benno
AU - Hu, Jiong
AU - Trouvain, Caroline
AU - Barbosa-Sicard, Eduardo
AU - Popp, Rüdiger
AU - Liebner, Stefan
AU - Dimmeler, Stefanie
AU - Hammock, Bruce D.
AU - Fleming, Ingrid
PY - 2012/6/19
Y1 - 2012/6/19
N2 - Fatty acid epoxides are important lipid signaling molecules involved in the regulation of vascular tone and homeostasis. Tissue and plasma levels of these mediators are determined by the activity of cytochrome P450 epoxygenases and the soluble epoxide hydrolase (sEH), and targeting the latter is an effective way of manipulating epoxide levels in vivo. We investigated the role of the sEH in regulating the mobilization and proliferation of progenitor cells with vasculogenic/reparative potential. Our studies revealed that sEH down-regulation/inhibition impaired the development of the caudal vein plexus in zebrafish, and decreased the numbers of lmo2/cmyb-positive progenitor cells therein. In mice sEH inactivation attenuated progenitor cell proliferation (spleen colony formation), but the sEH products 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME) and 11,12- dihydroxyeicosatrienoic acid stimulated canonicalWnt signaling and rescued the effects of sEH inhibition. In murine bone marrow, the epoxide/diol content increased during GCSF - induced progenitor cell expansion and mobilization, and both mobilization and spleen colony formation were reduced in sEH -/-mice. Similarly, sEH -/- mice showed impaired functional recovery following hindlimb ischemia, which was rescued following either the restoration of bone marrow sEH activity or treatment with 12,13-DiHOME. Thus, sEH activity is required for optimal progenitor cell proliferation, whereas long-term sEH inhibition is detrimental to progenitor cell proliferation, mobilization, and vascular repair.
AB - Fatty acid epoxides are important lipid signaling molecules involved in the regulation of vascular tone and homeostasis. Tissue and plasma levels of these mediators are determined by the activity of cytochrome P450 epoxygenases and the soluble epoxide hydrolase (sEH), and targeting the latter is an effective way of manipulating epoxide levels in vivo. We investigated the role of the sEH in regulating the mobilization and proliferation of progenitor cells with vasculogenic/reparative potential. Our studies revealed that sEH down-regulation/inhibition impaired the development of the caudal vein plexus in zebrafish, and decreased the numbers of lmo2/cmyb-positive progenitor cells therein. In mice sEH inactivation attenuated progenitor cell proliferation (spleen colony formation), but the sEH products 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME) and 11,12- dihydroxyeicosatrienoic acid stimulated canonicalWnt signaling and rescued the effects of sEH inhibition. In murine bone marrow, the epoxide/diol content increased during GCSF - induced progenitor cell expansion and mobilization, and both mobilization and spleen colony formation were reduced in sEH -/-mice. Similarly, sEH -/- mice showed impaired functional recovery following hindlimb ischemia, which was rescued following either the restoration of bone marrow sEH activity or treatment with 12,13-DiHOME. Thus, sEH activity is required for optimal progenitor cell proliferation, whereas long-term sEH inhibition is detrimental to progenitor cell proliferation, mobilization, and vascular repair.
KW - Beta-catenin
KW - Ischemic hindlimb
KW - Linoleic acid
UR - http://www.scopus.com/inward/record.url?scp=84862550071&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862550071&partnerID=8YFLogxK
U2 - 10.1073/pnas.1206493109
DO - 10.1073/pnas.1206493109
M3 - Article
C2 - 22665795
AN - SCOPUS:84862550071
VL - 109
SP - 9995
EP - 10000
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 25
ER -