Nitric oxide induces gelatinase A (matrix metalloproteinase 2) during rat embryo implantation

Objective: To evaluate a reciprocal signaling interaction initiated by embryo-derived nitric oxide (NO) to facilitate implantation by increased production of gelatinase A (matrix metalloproteinase 2, MMP2) in uterine stroma. Design: Experimental animal studies. Setting: Reproductive-physiology research laboratory. Animal(s): Female syngeneic Wistar rats aged 14 weeks. Intervention(s): Vaginal smears to confirm pregnancy. Oviductal ligature to avoid the descent of blastocysts to the uterine lumen. Plasma exudation assays to locate uterine blastocyst implantation sites. Organ cultures treated with NO donors and nitric oxide synthase (NOS) inhibitors. Main Outcome Measure(s): Expression of MMP2 and NO was assessed by Western blot and zymography of tissue extracts and by immunofluorescence of tissue sections. Result(s): An increase in MMP2 activity was found in uterine extracts in early pregnant rats and was concentrated at implantation sites. Immunolocalization experiments showed that inducible NOS was expressed on the surface of the implanting blastocyst adjacent to the uterine epithelium at the sites of increased MMP2 expression. In organ culture experiments, NO donors were found to increase, whereas NOS inhibitors were found to decrease MMP2 activity in uterine tissue sections. Conclusion(s): Blastocyst-derived NO contributes to the production of uterine-derived MMP2, an essential component of implantation and initiation of placentation.