Role of estrogen receptors in menstrual cycle-related neoangiogenesis and their influence on endothelial progenitor cell physiology.
OBJECTIVE
To study whether estrogen receptors (ERs) are expressed in vitro and in vivo by female circulating endothelial progenitor cells (EPCs); and the role of ERs in the periodic vascular damage and repair that occurs during the menstrual cycle.


METHODS
Quantification of circulating progenitor cells, EPCs, and relative CXCR4+ fraction by flow cytometry. Quantification of plasma 17beta-E(2) by electrochemiluminescent immunoassay. Expression of ERs by immunofluorescence and immunohistochemistry. Estrogen receptor, CXCR4, and matrix metalloproteinase 9 gene expression by reverse transcriptase-polymerase chain reaction and real-time polymerase chain reaction.


METHODS
University clinic and academic research laboratory.


METHODS
Twelve young fertile women (aged 22-27 years) observed for 6 months, 10 postmenopausal women (aged 52-63 years), and 50 male control subjects (aged 24-61 years).


METHODS
Blood (35 mL) was collected at each observation point.


METHODS
Correlation between 17beta-E(2) exposure and neoangiogenesis markers.


RESULTS
Estrogen receptors are expressed both in cultured EPCs after prolonged estrogen stimulation and in circulating EPCs, such as in CD34+ cells in bone marrow. The number of ER-beta+ and CXCR4+ EPCs increased during the ovulatory phase, and this increase is probably mediated by ER-beta and matrix metalloproteinase 9.


CONCLUSIONS
Estrogens play a key role in neoangiogenesis processes, such as endometrium recovery, and this mechanism involves both a central action (on bone marrow) and a cytokine-mediated peripheral one (on endothelium).
Foresta
Carlo
C
Department of Histology, Microbiology and Medical Biotechnologies, Center for Male Gamete Cryopreservation, University of Padova, Padova, Italy.
De Toni
Luca
L
Di Mambro
Antonella
A
Ferlin
Alberto
A
Perilli
Lisa
L
Bertuzzi
Ilaria
I
Galan
Alessandro
A
Zuccarello
Daniela
D
D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D004717:Endometrium / Q000098:blood supply*; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000097:blood* / Q000235:genetics; D047629:Estrogen Receptor beta / Q000097:blood* / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007118:Immunoassay; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008593:Menopause / Q000097:blood; D008597:Menstrual Cycle / Q000378:metabolism*; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D019718:Receptors, CXCR4 / Q000097:blood / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult
C527276:CXCR4 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D019718:Receptors, CXCR4; D004958:Estradiol; D020780:Matrix Metalloproteinase 9