Dynamic changes occur in patterns of endometrial EFNB2/EPHB4 expression during the period of spiral arterial modification in mice.

Transient, human and murine decidua-associated, Natural Killer lymphocytes (uNK cells) have special, localized roles in early gestational endometrial remodeling and angiogenesis. To determine if uNK cells promote a specific vessel subtype, a histological time-course study of implantation site endothelia was undertaken using normal C57BL/6J (B6) and uNK-deficient B6.129-Rag2 tm1Fwa Il2rg tm2Cgn (alymphoid) mice, a strain lacking pregnancy-induced structural modifications of spiral arteries. Antibodies to EFNB2, EPHB4, and LYVE1, respectively, identified arterial, venous, and lymphatic endothelia. Unexpectedly, many uNK cells in B6 endometrium showed strong EFNB2 expression early in gestation, then became EPHB4+. This molecular transition coincided with structural modifications of spiral arteries that shifted from EFNB2+/EPHB4(-) to EFNB2+/EPHB4+. NK cells from B6 spleen and liver did not express EFNB2. LYVE1 expression was similar in endometrium from B6 and alymphoid mice, but EFNB2 and EPHB4 expression in alymphoid mice was dramatically different. Strong stromal expression of both molecules developed mesometrially, and this was reduced by B6 lymphocyte transfer. Trophoblasts reacted with each marker in both strains. Expression of EFNB2 by uNK cells and trophoblasts may be the key regulatory mechanism that drives their positional association with EFNB2+ arteries and prevents association of both cell types with EPHB4+ veins. Gain of EPHB4 by midgestation spiral arteries may signal completion of pregnancy-induced arterial modification and provide a repulsion mechanism that limits subsequent interactions of the modified vessel with uNK cells and trophoblasts.