Levels of miR-451 detected in eutopic endometrium from women with endometriosis, may be a result of already established ectopic implants/ presence of existing endometriosis. To begin to assess the mechanisms by which miR-451 deficiency influences the ability of endometrial fragments to establish ectopically, we performed 2D-DiGE. From the differentially expressed proteins identified, we further focused on fibrinogen alpha polypeptide isoform 2 precursor which is an approximate 62 kDa protein derived from processing of the fibrinogen alpha chain. Fibrinogen alpha polypeptide isoform 2 precursor contains three RGD sequences. Based upon RGD content, fibrinogen alpha polypeptide isoform 2 precursor, would be more likely to displace in vivo VN binding to its respective integrin, avb3 allowing for adhesion/cell attachment. Our in vitro and in vivo studies using the RGD peptide antagonist, cyloRGDfV confirm that adhesion of endometrial stromal cells and mouse endometrial implant tissue occur via an RGD-dependent mechanism and that VN may be a major component of this adhesive mechanism. aVb3 is over-expressed in endometrial tissue from women with endometriosis and is proposed to play a role in the development of the disease. However, there is little evidence on the actual role of this integrin in the cell-cell mechanisms for establishment of ectopic lesions in vivo. A single report demonstrated that administration of an aVb3 blocking antibody inhibits growth of endometriosis in a mouse model for the disease but also reported an increase in lesion weight. As synthetic peptides containing the RGD motif are known to induce apoptosis, these agents may represent a novel approach to targeting existing disease and/or preventing the establishment of new ectopic lesions. This postulate prompted us to examine levels of plasmin activity in these tissues. Fibrinogen cleavage by plasmin releases several fragments from the fibrinogen molecule. Previously, we demonstrated that estrogen primed uterine tissue expressed elevated plasmin activity and a similar result was obtained in the current study in PMSG-primed mice. Thus, elevated plasmin activity in the endometrial fragments of miR-451 null mice may play a role in the degradation/reduction of total Fga protein characteristic of these fragments leading to an overall decrease in the expression of total Fga fragments in the null endometrial tissue. We propose that in both wild-type and null endometrial tissue, elevated plasmin activity may lead to loss/decrease in the relative abundance of the 95 kDa Fga molecule, while in the null tissue itself the significantly higher plasmin activity may lead to further selective degradation of the 34- and 42 kDa fragments but increased expression in the fibrinogen alpha polypeptide isoform 2 precursor. In summary, disruption of miR-451 expression in endometrial tissue impairs the ability of this tissue to establish ectopically in a mouse model of endometriosis.