Nitric Oxide Induces Gelatinase A (Matrix Metalloproteinase-2) during Rat Embryo Implantation

V. NOVARO; C. PUSTOVRH; A. COLMAN LERNER; D. RADISKY; F. LO NOSTRO; D. PAZ; A. JAWERBAUM; M. GIMENO; E. GONZALEZ

FERTILITY AND STERILITY

Elsevier

Lugar: NJ, USA; Año: 2002 vol. 76 p. 1278 - 1287

0015-0282

The embryo implantation process requires extensive remodeling of the maternal extracellular matrix so that the embryonic cells can invade the uterus wall to make contact and merge with the maternal vascular network. Here, we provide experiments that demonstrate that nitric oxide (NO), the well-known regulator of vascular permeability, also controls the location of implantation by stimulating the expression of the matrix metalloproteinases (MMPs) enzyme, gelatinase A (MMP2). We have previously shown that nitric oxide synthase (NOS) activity peaks during the periimplantation days of pregnancy. We now demonstrate a synchronized increase in MMP2 activity in uterine extracts from early pregnant rats and show that this activity is primarily localized to the implantation sites. Immunolocalization experiments show that inducible NOS (iNOS) is expressed on the surface of the implanting blastocyst adjacent to the uterine epithelium at the sites of increased MMP2 expression, suggesting that blastocyst-derived NO could be stimulating the production of uterine-derived MMP2, an essential component of implantation and initiation of placentation. This conclusion was validated by organ culture experiments in which NO donors were found to increase, whereas NOS inhibitors were found to decrease, MMP2 activity in uterine tissue sections.