Vascular-leukocyte interactions: mechanisms of human decidual spiral artery remodeling in vitro.

Transformation of uterine spiral arteries is critical for healthy human pregnancy. We recently proposed a role for maternal leukocytes in decidual spiral artery remodeling and suggested that matrix metalloprotease (MMP) activity contributed to the destruction of the arterial wall. In the current study we used our first trimester placental-decidual co-culture (PDC) model to define the temporal relationship and test the mechanistic aspects of this process. PDC experiments were assessed by image analysis over a six-day time-course for degree of vascular transformation and leukocyte distribution around progressively remodeled arterioles. We observed rapid transformation in PDCs associated with loss of vascular smooth muscle cells, widening of the vessel lumen, and significant accumulation of uterine Natural Killer cells and macrophages within the vascular wall (P < 0.001) before trophoblast presence in the vessel lumens. These events did not occur in decidua-only cultures. Active MMP-9 was detected in leukocytes and vascular cells of remodeling arterioles, and inhibition of MMP-2/9 activity in PDC resulted in failure of decidual vascular remodeling compared with vehicle-treated PDCs. Apoptosis of vascular cells, macrophage-mediated phagocytosis, and vascular smooth muscle cell dedifferentiation contributed to the remodeling observed. The PDC model indicates that placental presence is required to initiate decidual spiral artery remodeling but that uterine Natural Killer cells and macrophages mediate the early stages of this process at the cellular level.

Aberrant endometrial features of pregnancy in diabetic NOD mice.

OBJECTIVE: Pregnant diabetic women are at a 4-12 times higher risk for preeclampsia, an urgent acute-onset complication of mid- to late gestation, than normal pregnant women. Hallmarks of preeclampsia are hypertension, proteinuria, and incomplete modification of endometrial spiral arteries. Transient proangiogenic 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 investigate whether diabetes alters uNK cell homing and/or function. RESEARCH DESIGN AND METHODS: Normoglycemic, pre-diabetic, 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 placentas, and lighter fetuses displaying numerous birth defects compared with controls. UNK cell numbers were reduced in the decidua basalis of diabetic females, whereas interferon-gamma production was elevated. In diabetic NOD mice, decidual expression of the mucosal vascular addressin cell adhesion molecule (MAdCAM)-1 was aberrant in position, whereas vascular cell adhesion molecule (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 contribute to murine fetal loss and birth defects. Analogous problems and preeclampsia in diabetic women may involve similar mechanisms.