Studies on the alpha-2 macroglobulin gene family in pregnant mouse uterus.

摘要

Uterine Natural Killer (uNK) cells are the dominant lymphocytes in the pregnant mouse uterus. Their precursors migrate from secondary lymphoid tissues during decidualization and localize in mesometrial decidua for terminal proliferation and differentiation. Uterine NK cells reach peak numbers by mid-gestation. Interferon (IFN)-γ is a major uNK cell-derived cytokine that regulates genes promoting spiral artery wall thinning and dilation. However, the genes targeted in the vasculature are as yet undefined. Complimentary DNA microarray analysis and northern analysis of mesometrial decidua (days 6 & 10) from C57BL/6 mice showed increased expression of two alpha-2 macroglobulin (α2M) gene family members; Mouse α2M (MAM) and a novel member (α2MX). The goal of this study was to begin to characterize the role of the α2M gene family in mouse pregnancy. Implantation sites of mice dually deficient for MAM and Murinoglobulin-I (MAM−/−/MUG-1 −/−), the two most abundantly expressed members of the α2M gene family, had reduced uNK cell numbers, poor decidual development and spiral arteries with unusual cuffs of trophoblast-like cells. Pregnant alymphoid mice, characterized by no uNK cells, decidual hypocellularity and unmodified spiral arteries, were infused with increasing doses of human α2M to assay potential activity. Morphometric analyses showed increased decidual cell numbers and stepwise, dose-dependent spiral artery modification representing dilation, elongation and branching. In-situ hybridization and RT-PCR analysis showed the spatial and temporal distribution of α2MX. These studies suggest that pregnancy-induced α2Ms play an essential role in spiral artery remodeling through the binding and regulation of cytokine milieu at the remodeling site.