AbstractWe 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.
