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Endometrial -2 Macroglobulin; Localization by in Situ Hybridization and Effect on Mouse Embryo Development in Vitro¹

Vincent Memorial Obstetrics and Gynecology Service, Division of Reproductive Endocrinology and Infertility, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Keith Isaacson, M.D., Vincent Memorial Obstetrics and Gynecology Service, Wang Ambulatory Care Center II, Massachusetts General Hospital, Boston, Massachusetts 02114.

-2 macroglobulin (A2M) is a 718,000-kDa broad spectrum plasma protease inhibitor whose production by the human endometrium was recently reported. The multifunctional A2M receptor, also known as low-density lipoprotein receptor-related protein, was also recently immunolocalized to the endometrial stroma. The objective of this study was to further characterize the endometrial site of expression of A2M, and to study its effects on mouse embryo development in vitro, to gain some insight into the functional significance of its endometrial production.

Formalin-fixed, paraffin-embedded human endometrium from hysterectomy and endometrial biopsy specimen was used for in situ hybridization analysis, with ³⁵S-labeled riboprobes representing subcloned A2M complementary DNA (cDNA) fragments. Duplicate sections of human endometrium were hybridized with sense and antisense probe and coated with photographic emulsion. Resultant autoradiograms were analyzed qualitatively by light- and darkfield microscopy and quantitatively by a computerized analysis of the signal intensity. Immunohistochemistry and immunoblotting for endometrial tissues were performed using an affinity-purified polyclonal antibody to human A2M. The effect of A2M on mouse embryo development was studied by exposure of one cell mouse embryo in culture to physiological concentrations of biologically active and inactive A2M.

Expression signals for A2M were more numerous and intense in the secretory endometrium, compared with proliferative endometrium. Endothelial cells lining the endometrial blood vessels seemed to be the main source of A2M expression. The A2M expression signals in secretory endothelium were 2- to 3-fold stronger than the proliferative endothelium, suggesting transcriptional activation of A2M expression in the secretory endothelium. Glandular expression was observed in secretory endometrium from two patients with endometriosis. Ectopic endometrial tissues also produced A2M. A2M at concentrations of 400–500 µmol/L significantly inhibited blastocyst development of mouse embryos in vitro.

A2M is expressed predominantly by the endometrial endothelial cells and may be involved in endometrial physiology. Physiological concentrations of A2M inhibit mouse embryo development in vitro, suggesting that endometrial production of A2M may play a role in regulating preimplantation embryo development.

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