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(Circulation Research. 2007;101:598.)
© 2007 American Heart Association, Inc.

Cellular Biology

Estrogen-Mediated Endothelial Progenitor Cell Biology and Kinetics For Physiological Postnatal Vasculogenesis

Haruchika Masuda, Christoph Kalka, Tomono Takahashi, Miyoko Yoshida, Mika Wada, Michiru Kobori, Rie Itoh, Hideki Iwaguro, Masamichi Eguchi, Yo Iwami, Rica Tanaka, Yoshihiro Nakagawa, Atsuhiko Sugimoto, Sayaka Ninomiya, Shinichiro Hayashi, Shunichi Kato, Takayuki Asahara

From the Department of Regenerative Medicine (H.M., M.Y., M.W., M.K., R.I., H.I., M.E., Y.I., R.T., Y.N., A.S., S.N., S.K., T.A.), Tokai University School of Medicine, Isehara, Japan; the Department of Vascular Medicine (C.K.), Swiss Cardiovascular Center, University Hospital of Bern, Switzerland; the third Department of Internal Medicine (T.T.), Tokyo Medical University, Japan; the Department of Cell Signaling (S.H.), Gifu University Graduate School of Medicine, Japan.; Stem Cell Translational Research (T.A.), Institute of Biomedical Research and Innovation/ RIKEN Center for Developmental Biology, Kobe, Japan.

Correspondence to Takayuki Asahara, MD, PhD, Department of Regenerative Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan. E-mail asa777{at}aol.com

Estrogen has been demonstrated to promote therapeutic reendothelialization after vascular injury by bone marrow (BM)–derived endothelial progenitor cell (EPC) mobilization and phenotypic modulation. We investigated the primary hypothesis that estrogen regulates physiological postnatal vasculogenesis by modulating bioactivity of BM-derived EPCs through the estrogen receptor (ER), in cyclic hormonally regulated endometrial neovascularization. Cultured human EPCs from peripheral blood mononuclear cells (PB-MNCs) disclosed consistent gene expression of ER as well as downregulated gene expressions of ER ß. Under the physiological concentrations of estrogen (17ß-estradiol, E2), proliferation and migration were stimulated, whereas apoptosis was inhibited on day 7 cultured EPCs. These estrogen-induced activities were blocked by the receptor antagonist, ICI182,780 (ICI). In BM transplanted (BMT) mice with ovariectomy (OVX) from transgenic mice overexpressing ß-galactosidase (lacZ) regulated by an endothelial specific Tie-2 promoter (Tie-2/lacZ/BM), the uterus demonstrated a significant increase in BM-derived EPCs (lacZ expressing cells) incorporated into neovasculatures detected by CD31 immunohistochemistry after E2 administration. The BM-derived EPCs that were incorporated into the uterus dominantly expressed ER , rather than ER ß in BMT mice from BM of transgenic mice overexpressing EGFP regulated by Tie-2 promoter with OVX (Tie-2/EGFP/BMT/OVX) by ERs fluorescence immunohistochemistry. An in vitro assay for colony forming activity as well as flow cytometry for CD133, CD34, KDR, and VE-cadherin, using human PB-MNCs at 5 stages of the female menstrual-cycle (early-proliferative, pre-ovulatory, post-ovulatory, mid-luteal, late-luteal), revealed cycle-specific regulation of EPC kinetics. These findings demonstrate that physiological postnatal vasculogenesis involves cyclic, E2-regulated bioactivity of BM-derived EPCs, predominantly through the ER.

Key Words: estrogen • endothelial progenitor cell • estrogen receptor • physiological postnatal vasculogenesis

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