Estradiol-induced, endothelial progenitor cell-mediated neovascularization in male mice with hind-limb ischemia.
We investigated whether administration of estradiol to male mice augments mobilization of bone marrow-derived endothelial progenitor cells (EPC) and incorporation into foci of neovascularization after hind-limb ischemia, thereby contributing to blood flow restoration. Mice were randomized and implanted with placebo pellets or pellets containing low-dose estradiol (0.39 mg) or high-dose estradiol (1.7 mg). Hind-limb ischemia was induced by unilateral resection of the left femoral artery 1 week after pellet implantation, then EPC mobilization and functional recovery was evaluated. EPC recruitment was assessed in mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase driven by the Tie-2 promoter. EPC culture assay performed 2 weeks after pellet implantation revealed a significantly greater (p<0.05) number of circulating EPCs in the high-dose estradiol group than in the low-dose estradiol and placebo groups. At 3 and 4 weeks after induction of hind-limb ischemia, perfusion was significantly greater (p<0.05) in high-dose estradiol mice than in mice implanted with the low-dose estradiol or placebo pellets. At 1 and 4 weeks after hind-limb ischemia surgery, more bone marrow-derived EPCs, identified as beta-galactosidase-positive cells, were observed in ischemic regions from high-dose estradiol animals than in low-dose (p<0.05) or placebo groups (p<0.05). These results indicate that estradiol dose-dependently increases the levels of EPCs in peripheral blood in male animals, improves the recovery of blood flow, and decreases limb necrosis after hind-limb ischemia, and that this enhancement occurs, in part, through augmentation of EPC mobilization and greater incorporation of bone marrow-derived EPCs into foci of neovascularization.
Ruifrok
Willem-Peter T
WP
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
de Boer
Rudolf A
RA
Iwakura
Atsushi
A
Silver
Marcy
M
Kusano
Kengo
K
Tio
Rene A
RA
Losordo
Douglas W
DW
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000201:enzymology; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004958:Estradiol / Q000008:administration & dosage*; D006614:Hindlimb; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000473:pathology; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D042787:Receptor, TIE-2 / Q000235:genetics; D012039:Regional Blood Flow / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D043925:Angiogenesis Inducing Agents; D004343:Drug Implants; D004958:Estradiol; D042787:Receptor, TIE-2; D001616:beta-Galactosidase