Estrogen-mediated endothelial progenitor cell biology and kinetics for physiological postnatal vasculogenesis.
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 alpha as well as downregulated gene expressions of ER beta. Under the physiological concentrations of estrogen (17beta-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 beta-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 alpha, rather than ER beta 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 alpha.
Department of Regenerative Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan.
Haruchika
H
Masuda
Christoph
C
Kalka
Tomono
T
Takahashi
Miyoko
M
Yoshida
Mika
M
Wada
Michiru
M
Kobori
Rie
R
Itoh
Hideki
H
Iwaguro
Masamichi
M
Eguchi
Yo
Y
Iwami
Rica
R
Tanaka
Yoshihiro
Y
Nakagawa
Atsuhiko
A
Sugimoto
Sayaka
S
Ninomiya
Shinichiro
S
Hayashi
Shunichi
S
Kato
Takayuki
T
Asahara
D000328:Adult; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D002478:Cells, Cultured; D016510:Corneal Neovascularization / Q000378:metabolism; D004717:Endometrium / Q000098:blood supply* / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007700:Kinetics; D008597:Menstrual Cycle / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010052:Ovariectomy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D000077267:Fulvestrant; D004958:Estradiol; D042787:Receptor, TIE-2