Uterine natural killer cells and angiogenesis in recurrent reproductive failure.
BACKGROUND
Increased numbers of phenotypically unusual CD56(bright) CD16- uterine natural killer (uNK) cells have been associated with recurrent reproductive failure. uNK cells produce angiogenic growth factors and are potential regulators of decidual angiogenesis in early pregnancy. The final common mechanism for early pregnancy loss is thought to be early onset of the maternal circulation and excessive placental oxidative stress. We tested the hypothesis that increased uNK cells in preimplantation endometrium are associated with altered angiogenesis.


METHODS
Women with recurrent reproductive failure (n = 122) were investigated with uterine artery Doppler and endometrial biopsy. Immunohistochemistry was used to identify uNK, endothelial and vascular smooth muscle cells and image analysis was used to assess location, density and differentiation.


RESULTS
uNK cell density was positively correlated with the formation of blood (P = 0.005, r = 0.5) and lymphatic vessels (P = 0.0001, r = 0.6), spiral arteriole smooth muscle differentiation (P = 0.01, r = 0.5) and endometrial oedema (P = 0.004). The functional effect of this was a reduced uterine artery resistance to blood flow.


CONCLUSIONS
These data suggest that uNK cells may regulate angiogenesis in non-pregnant endometrium. The mechanisms of reproductive failure associated with increased uNK cell density appear to be increased angiogenesis and peri-implantation blood flow, which may lead to early maternal circulation and hence pregnancy failure due to excessive oxidative stress.
School of Reproductive and Developmental Medicine, University of Liverpool, First Floor, Liverpool Women's Hospital, Crown Street, Liverpool L8 7SS, UK. squenby@liv.ac.uk
Siobhan
S
Quenby
Helena
H
Nik
Barbara
B
Innes
Gendie
G
Lash
Mark
M
Turner
Jo
J
Drury
Judith
J
Bulmer
D000026:Abortion, Habitual / Q000097:blood* / Q000000981:diagnostic imaging / Q000473:pathology; D000328:Adult; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D018384:Oxidative Stress; D011247:Pregnancy; D012039:Regional Blood Flow; D018608:Ultrasonography, Doppler; D014599:Uterus / Q000098:blood supply / Q000166:cytology* / Q000000981:diagnostic imaging