The Network Of Cytokines,Extracellular Matrix,Integrins And Matrix Metalloproteinases During Early Implantation In Mouse

Implantation of the embryo into the lumenal epithelium of the endometrium is one of the most important steps in the establishment of intimate maternal-fetal connection and in the maintenance of a viable pregnancy. Successiful implantation depends on invasive blastocyst, acceptive endometrium and their synchronization. It is documented that maternal steroids, prostaglandins, chronic gonadotropin, cytokines, adhesion molecules, proteinases and proteinase inhibitors are involved in the complex process. Immerse evidence implied that the modulators may integrate into a network modulating implantation spatially and temporily. However, the frame of the network has not been well outlined yet. The present study is aimed at acquiring new evidence for the network by defining the interactions between leukemia inhibitory factor, epidermal growth factor. interleukin- I beta, fibronectin and its integrin receptors as well as marix metolloproteinases. The results show that fibronectin, an important extracellular matrix, not only enhances the blastocyst adhesion and outgrowth, also triggers the matrix metolloproteinases-2 and -9 activity. Its fttnction is dependent on its integrin receptors and intracellular signal transduction pathway, since the basic molecule of integrin-dependent intracellular signal transduction pathway focal adhesion kinase influences the blastocyst adhesion, outgrowth and matrix metolloproteinase activity triggered by fibronectin. The zymography and in vitro 53 implantation model show that LW EGF and IL-i beta do not influence balstocyst adhesion, outgrowth and matrix metalloproteinase activity while without fibronectin. On the contrast, they promote blastocyst adhesion, outgrowth and matrix metalloproteinases activity, and advance matrix metalloproteinases activity significantly, indicating the synchronization between the functions of LIF, EGF, IL-i beta, fibronectin and its integrin receptors. The indirect immunofluorecent assay show that LW EGF and IL-I beta increase the integrin alphavbeta3 expression and distribution on the surface of balstocyst, indicating that the function of LIF, EGF and IlL-i beta regulating blastocyst adhesion and outgrowth at least partially attributes to their effects on integrin expression and distribution. In conclusion, the present study evidences that cytokines, extracellular matrix, integrins and metalloproteinases do integrate into a delicate network to regulate spatially and temporally early implantation in mouse. Briefly, cytokines increase and, in turn, stimulate the relative integrin expression and distribution, resulting in enhancement of blastocyst adhesive invasive ability during preimplantation. Anyhow, blastocysts do not acquire the invasive ability until the interactions of extracellular matrix and integrins mediate them adhesing to endometrium epithelium, since the process triggers the matrix metalloproteinases activity which consisits the main invasive ability of blastocysts. Meanwhile, the synchronization between cytokine receptor signal transduction pathways and integrin-dependent signal transduction pathways enables increased cytokines to promote blastocyst adhesion and outgrowth and to increase and advance the matrix metalloproteinases activity, leading to the full adhesive and invasive abilities of blastocyst. The network ensures the synshronization of balstocyst and endometrium, and keeps the tight linkage between the adhesion and invasion steps of implantation spatially and temporally.