Aberrant Endometrial Features of Pregnancy in Diabetic NOD Mice

Abstract

Objective: Pregnancies in diabetic women are at 4-12 more risk for pre-eclampsia, an urgent, acute onset complication of mid to late gestation, than pregnancies in normal women. Hallmarks of pre-eclampsia are hypertension, proteinuria and incomplete modification of endometrial spiral arteries. Transient, pro-angiogenic lymphocytes called uterine Natural Killer (uNK) cells are implicated in human and rodent spiral artery modification. We studied mid to late gestations in spontaneously type 1 diabetic NOD mice to ask if diabetes alters uNK cell homing and/or function.

Research design and method: Normoglycemic, prediabetic and diabetic NOD mice and controls were mated. Lymphocytes and endometrial endothelium and decidua were studied histologically and in functional assays.

Results: Conception accelerated progression to overt diabetes in NOD females who had limited spiral artery development, heavier placentae and lighter fetuses displaying numerous birth defects compared with controls. UNK cell numbers were reduced in the decidua basalis of diabetic females while interferon-γ production was elevated. In diabetic NOD mice, decidual expression of the endothelial cell addressin MAdCAM-1 was aberrant in position while VCAM-1 expression was reduced. Assays of lymphocyte adhesion to tissue sections under shear forces indicated that diabetes compromises the potential homing functions of both endometrial endothelium and peripheral NK cells.

Conclusions: In diabetes, gestational endometrium has immune and vascular defects that likely to contribute to murine fetal loss and birth defects. Analogous problems and pre-eclampsia in diabetic women may involve similar mechanisms.