Remodelling of the Uterine Matrix at Implantation

Rider, Virginia

Abstract

After ovulation, the mammalian uterus is reorganized to prepare for implantation of the blastocyst. This includes changes in the three types of endometrial tissues namely the luminal epithelium, glandular epithelium and stroma, each of which serves a different function at implantation. Cellular production of growth factors and/or connective tissue matrices is likely to be regulated during remodelling of the uterus since these molecules play key roles in modulating cellular proliferation and directing spatial organization of cells. In particular, the gene encoding fibronectin is a good candidate for such regulation because fibronectin protein levels and conformational arrangements have been observed to fluctuate during decidualization. As the corpus luteum becomes established, peripheral progesterone concentrations increase and cells in mitoses switch from the epithelium to the stroma. Stromal cell proliferation is dependent upon progesterone and it is coupled temporally with vascular growth and development in the uterus. While the precise mechanism by which growth factors promote cell proliferation is unclear, the ability of basic fiboblast growth factor (bFGF) to stimulate capillary endothelial cells and form new blood vessels has been firmly established. It is proposed that immunological and histological methods will be used in combination with molecular biology to reveal changes in total fibronectin mRNA and its isoforms, as well as changes in bFGF protein and total RNA, during the process of decidualization and implantation. The experiments described in this proposal are designed to contribute towards understanding the molecular mechanisms underlying previously observed changes in fibronectin during decidualization and early pregnancy and to assess the role of steroid hormones and bFGF in the remodelling of the uterine matrix. The results of the proposed studies will begin to elucidate the factors that regulate matrix remodelling in the mammalian uterus and as such will contribute to understanding failures of decidualization and implantation. These findings will also be important to other systems where similar, extensive matrix remodelling occurs such as wound healing and neoplastic transformation.