Estrogen-mediated endothelial progenitor cell biology and kinetics for physiological postnatal vasculogenesis

Circ Res. 2007 Sep 14;101(6):598-606. doi: 10.1161/CIRCRESAHA.106.144006. Epub 2007 Jul 26.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Apoptosis
  • Bone Marrow Transplantation
  • Cell Movement
  • Cell Proliferation*
  • Cell Shape
  • Cells, Cultured
  • Corneal Neovascularization / metabolism
  • Endometrium / blood supply*
  • Endometrium / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Estradiol / analogs & derivatives
  • Estradiol / metabolism*
  • Estradiol / pharmacology
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism
  • Female
  • Fulvestrant
  • Humans
  • Kinetics
  • Menstrual Cycle / metabolism
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Mice, Transgenic
  • Neovascularization, Physiologic* / drug effects
  • Ovariectomy
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism
  • Stem Cells / drug effects
  • Stem Cells / metabolism*

Substances

  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • RNA, Messenger
  • Fulvestrant
  • Estradiol
  • Receptor, TIE-2