Estradiol-induced, endothelial progenitor cell-mediated neovascularization in male mice with hind-limb ischemia.

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 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.

• Authors: Willem-Peter T Ruifrok, Rudolf A de Boer, Atsushi Iwakura, Marcy Silver, Kengo Kusano, Rene A Tio, Douglas W Losordo
• Journal: Vascular medicine (London, England) (Vasc Med) Vol. 14 Issue 1 Pg. 29-36 (Feb 2009) ISSN: 1358-863X [Print] England
• PMID: 19144777 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Drug Implants
• Estradiol
• Receptor, TIE-2
• beta-Galactosidase

Topics

• Angiogenesis Inducing Agents (administration & dosage)
• Animals
• Bone Marrow Cells (drug effects, enzymology)
• Bone Marrow Transplantation
• Capillaries (drug effects, physiopathology)
• Cell Movement (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Implants
• Endothelial Cells (drug effects, enzymology)
• Estradiol (administration & dosage)
• Hindlimb
• Ischemia (drug therapy, pathology, physiopathology)
• Male
• Mice
• Mice, Transgenic
• Muscle, Skeletal (blood supply, pathology)
• Necrosis
• Neovascularization, Physiologic (drug effects)
• Promoter Regions, Genetic
• Receptor, TIE-2 (genetics)
• Regional Blood Flow (drug effects)
• Stem Cells (drug effects, enzymology)
• Time Factors
• beta-Galactosidase (biosynthesis, genetics)