Angiogenic responses in the pregnant mouse uterus under uNK cell deletion and hypoxia

Eliana Mara Oliveira Lippe

Abstract
Inadequate uterine vascular remodeling is associated with pregnancy complication. Pregnancy specific uterine Natural Killer (uNK) cells produce angiogenic factors such as vascular endothelial growth factor (VEGF), nitric oxide (NO) and interferon-γ (IFNγ), but hypoxic effects of uNK cell functions are unknown. Here, we investigated the effects of hypoxia on murine uNK cell driven vascular remodeling and on pregnancy outcome. At gestational day (gd) 7.5, normal CD1 mice and genetically-modified IL-15-/- mice that lack uNK cells were exposed to 48 h of 420 Torr hypoxia. Pregnancies were then assessed at gestation day (gd) 9.5 for decidual gene and protein expression, histopathology or litter size at birth. Hypoxia delayed CD1 fetal development, but term deliveries occurred, with the exception in IL-15-/- uNK deficient mice. VEGF protein and gene expressions were down-regulated, but not abrogate in the uNK deficient mice, suggesting an alternative source of this angiogenic factor independent of uNK cell. High eNOS/iNOS expression seems to be uterine compensatory response in the uNK deficient mice and it is probably by increasing NO release to stimulate local angiogenesis. The reduced successful pregnancy outcome is not related to uNK cell cytotoxic activity. Otherwise, the high incidence of pregnancy failure of IL-15-/- animals confirmed the benefit of uNK cells in the homeostasis of pregnant uteri.

Keywords
Angiogenesis; Hypoxia; uNK cells; Uterine plasticity.

DOI
10.21472/bjbs.050902

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