Limits...
miR-451 deficiency is associated with altered endometrial fibrinogen alpha chain expression and reduced endometriotic implant establishment in an experimental mouse model.

Nothnick WB, Graham A, Holbert J, Weiss MJ - PLoS ONE (2014)

Bottom Line: MicroRNAs, small non-coding RNAs that post-transcriptionally regulate gene expression, are mis-expressed in endometriosis but a functional role in the disease pathogenesis remains uncertain.After induction of the disease, we evaluated the impact of this deficiency on implant development and survival.Loss of miR-451 expression resulted in a lower number of ectopic lesions established in vivo.

View Article: PubMed Central - PubMed

Affiliation: University of Kansas Medical Center, Department of Molecular & Integrative Physiology, Kansas City, Kansas, United States of America.

ABSTRACT
Endometriosis is defined as the growth of endometrial glandular and stromal components in ectopic locations and affects as many as 10% of all women of reproductive age. Despite its high prevalence, the pathogenesis of endometriosis remains poorly understood. MicroRNAs, small non-coding RNAs that post-transcriptionally regulate gene expression, are mis-expressed in endometriosis but a functional role in the disease pathogenesis remains uncertain. To examine the role of microRNA-451 (miR-451) in the initial development of endometriosis, we utilized a novel mouse model in which eutopic endometrial fragments used to induce endometriosis were deficient for miR-451. After induction of the disease, we evaluated the impact of this deficiency on implant development and survival. Loss of miR-451 expression resulted in a lower number of ectopic lesions established in vivo. Analysis of differential protein profiles between miR-451 deficient and wild-type endometrial fragments revealed that fibrinogen alpha polypeptide isoform 2 precursor was approximately 2-fold higher in the miR-451 donor endometrial tissue and this elevated expression of the protein was associated with altered expression of the parent fibrinogen alpha chain mRNA and protein. As this polypeptide contains RGD amino acid "cell adhesion" motifs which could impact early establishment of lesion development, we examined and confirmed using a cyclic RGD peptide antagonist, that endometrial cell adhesion and endometriosis establishment could be respectively inhibited both in vitro and in vivo. Collectively, these results suggest that the reduced miR-451 eutopic endometrial expression does not enhance initial establishment of these fragments when displaced into the peritoneal cavity, that loss of eutopic endometrial miR-451 expression is associated with altered expression of fibrinogen alpha chain mRNA and protein, and that RGD cyclic peptide antagonists inhibit establishment of endometriosis development in an experimental mouse model suggesting that this approach may prove useful in the prevention of endometriosis establishment and survival.

Show MeSH

Related in: MedlinePlus

RGD cycle peptide inhibits development of experimental endometriosis.Experimental endometriosis was induced in wild-type mice with wild-type endometrial fragments which were pre-treated with either vehicle (Veh) or RGD peptide (RGD) and development of ectopic lesions was assessed as described under “Materials and Methods.” Data are displayed as the mean ± SEM. Different letters indicate statistically significant differences among the means between treatments as determined by unpaired t-tests (N = 8/group). B Chi square analysis of the proportion of mice which received implant tissue pre-treated with either vehicle (Veh) or RGD cyclic peptide (RGD).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4061076&req=5

pone-0100336-g007: RGD cycle peptide inhibits development of experimental endometriosis.Experimental endometriosis was induced in wild-type mice with wild-type endometrial fragments which were pre-treated with either vehicle (Veh) or RGD peptide (RGD) and development of ectopic lesions was assessed as described under “Materials and Methods.” Data are displayed as the mean ± SEM. Different letters indicate statistically significant differences among the means between treatments as determined by unpaired t-tests (N = 8/group). B Chi square analysis of the proportion of mice which received implant tissue pre-treated with either vehicle (Veh) or RGD cyclic peptide (RGD).

Mentions: To determine if the RGD cyclic peptide could also influence the ability of endometrial fragments to establish ectopically in vivo, we pretreated endometrial fragments from wild-type mice with 100 µM of cyclic RGD peptide or vehicle for 1 h then transferred the fragments to wild-type recipients (N = 8 per treatment). Two weeks post endometriosis induction, the number of implants which developed were assessed (Fig. 7). Mice receiving endometrial fragments pre-treated with the RGD cyclic peptide had significantly fewer implants compared to mice receiving vehicle pre-treated implants (Fig. 7A). Further, significantly less mice which received the RGD peptide pre-treated implants developed implants (1/8 vs. 7/8 by chi square analysis; Fig. 7B).


miR-451 deficiency is associated with altered endometrial fibrinogen alpha chain expression and reduced endometriotic implant establishment in an experimental mouse model.

Nothnick WB, Graham A, Holbert J, Weiss MJ - PLoS ONE (2014)

RGD cycle peptide inhibits development of experimental endometriosis.Experimental endometriosis was induced in wild-type mice with wild-type endometrial fragments which were pre-treated with either vehicle (Veh) or RGD peptide (RGD) and development of ectopic lesions was assessed as described under “Materials and Methods.” Data are displayed as the mean ± SEM. Different letters indicate statistically significant differences among the means between treatments as determined by unpaired t-tests (N = 8/group). B Chi square analysis of the proportion of mice which received implant tissue pre-treated with either vehicle (Veh) or RGD cyclic peptide (RGD).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061076&req=5

pone-0100336-g007: RGD cycle peptide inhibits development of experimental endometriosis.Experimental endometriosis was induced in wild-type mice with wild-type endometrial fragments which were pre-treated with either vehicle (Veh) or RGD peptide (RGD) and development of ectopic lesions was assessed as described under “Materials and Methods.” Data are displayed as the mean ± SEM. Different letters indicate statistically significant differences among the means between treatments as determined by unpaired t-tests (N = 8/group). B Chi square analysis of the proportion of mice which received implant tissue pre-treated with either vehicle (Veh) or RGD cyclic peptide (RGD).
Mentions: To determine if the RGD cyclic peptide could also influence the ability of endometrial fragments to establish ectopically in vivo, we pretreated endometrial fragments from wild-type mice with 100 µM of cyclic RGD peptide or vehicle for 1 h then transferred the fragments to wild-type recipients (N = 8 per treatment). Two weeks post endometriosis induction, the number of implants which developed were assessed (Fig. 7). Mice receiving endometrial fragments pre-treated with the RGD cyclic peptide had significantly fewer implants compared to mice receiving vehicle pre-treated implants (Fig. 7A). Further, significantly less mice which received the RGD peptide pre-treated implants developed implants (1/8 vs. 7/8 by chi square analysis; Fig. 7B).

Bottom Line: MicroRNAs, small non-coding RNAs that post-transcriptionally regulate gene expression, are mis-expressed in endometriosis but a functional role in the disease pathogenesis remains uncertain.After induction of the disease, we evaluated the impact of this deficiency on implant development and survival.Loss of miR-451 expression resulted in a lower number of ectopic lesions established in vivo.

View Article: PubMed Central - PubMed

Affiliation: University of Kansas Medical Center, Department of Molecular & Integrative Physiology, Kansas City, Kansas, United States of America.

ABSTRACT
Endometriosis is defined as the growth of endometrial glandular and stromal components in ectopic locations and affects as many as 10% of all women of reproductive age. Despite its high prevalence, the pathogenesis of endometriosis remains poorly understood. MicroRNAs, small non-coding RNAs that post-transcriptionally regulate gene expression, are mis-expressed in endometriosis but a functional role in the disease pathogenesis remains uncertain. To examine the role of microRNA-451 (miR-451) in the initial development of endometriosis, we utilized a novel mouse model in which eutopic endometrial fragments used to induce endometriosis were deficient for miR-451. After induction of the disease, we evaluated the impact of this deficiency on implant development and survival. Loss of miR-451 expression resulted in a lower number of ectopic lesions established in vivo. Analysis of differential protein profiles between miR-451 deficient and wild-type endometrial fragments revealed that fibrinogen alpha polypeptide isoform 2 precursor was approximately 2-fold higher in the miR-451 donor endometrial tissue and this elevated expression of the protein was associated with altered expression of the parent fibrinogen alpha chain mRNA and protein. As this polypeptide contains RGD amino acid "cell adhesion" motifs which could impact early establishment of lesion development, we examined and confirmed using a cyclic RGD peptide antagonist, that endometrial cell adhesion and endometriosis establishment could be respectively inhibited both in vitro and in vivo. Collectively, these results suggest that the reduced miR-451 eutopic endometrial expression does not enhance initial establishment of these fragments when displaced into the peritoneal cavity, that loss of eutopic endometrial miR-451 expression is associated with altered expression of fibrinogen alpha chain mRNA and protein, and that RGD cyclic peptide antagonists inhibit establishment of endometriosis development in an experimental mouse model suggesting that this approach may prove useful in the prevention of endometriosis establishment and survival.

Show MeSH
Related in: MedlinePlus