Estradiol-induced, endothelial progenitor cell-mediated neovascularization in male mice with hind-limb ischemiaDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Division of Cardiovascular Research, St Elizabeth’s Medical Center, Tufts University Medical School, Boston, MA, USA
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Division of Cardiovascular Research, St Elizabeth’s Medical Center, Tufts University Medical School, Boston, MA, USA
Division of Cardiovascular Research, St Elizabeth’s Medical Center, Tufts University Medical School, Boston, MA, USA
Division of Cardiovascular Research, St Elizabeth’s Medical Center, Tufts University Medical School, Boston, MA, USA
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA d-losordo{at}northwestern.edu Abstract 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 β-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 β-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.
Key Words: angiogenesis • endothelial progenitor cell • estrogen • neovascularization
Vascular Medicine, Vol. 14, No. 1,
29-36 (2009) |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
|
 |
|
