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 withrecurrent reproductive failure. uNK cells produce angiogenicgrowth factors and are potential regulators of decidual angiogenesisin early pregnancy. The final common mechanism for early pregnancyloss is thought to be early onset of the maternal circulationand excessive placental oxidative stress. We tested the hypothesisthat increased uNK cells in preimplantation endometrium areassociated with altered angiogenesis. METHODS: Women with recurrent reproductive failure (n = 122) were investigatedwith uterine artery Doppler and endometrial biopsy. Immunohistochemistrywas used to identify uNK, endothelial and vascular smooth musclecells and image analysis was used to assess location, densityand differentiation. RESULTS: uNK cell density was positively correlated with the formationof 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 functionaleffect of this was a reduced uterine artery resistance to bloodflow. CONCLUSIONS: These data suggest that uNK cells may regulate angiogenesisin non-pregnant endometrium. The mechanisms of reproductivefailure associated with increased uNK cell density appear tobe increased angiogenesis and peri-implantation blood flow,which may lead to early maternal circulation and hence pregnancyfailure due to excessive oxidative stress.