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Successful ovulation in plasminogen-deficient mice treated with the broad-spectrum matrix metalloproteinase inhibitor galardin.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2006 (English)In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 295, no 2, 615-622 p.Article in journal (Refereed) Published
Abstract [en]

Many studies have suggested the hypothesis that the plasminogen activator (PA) system and the matrix metalloproteinase (MMP) system, either separately or in combination, may provide the proteolytic activity that is required for rupture of the follicular wall at the time of ovulation. Our recent studies on ovulation in plasminogen (plg)-deficient mice have, however, shown that plasmin is not required for normal ovulation, leading us to the hypothesis that MMPs may be a more important source of proteolysis for this process. To investigate the role of MMPs and also the possibility of a functional overlap or synergy between the MMP and PA systems during ovulation, we have studied ovulation efficiency in wild-type and plg-deficient mice treated with the broad-spectrum MMP inhibitor galardin. We found that in both wild-type mice and heterozygous plg-deficient (plg(+/-)) mice that had been treated with galardin prior to ovulation, there was a mild (18-20%) reduction in ovulation efficiency. Surprisingly, galardin treatment of plg-deficient (plg(-/-)) mice only caused an additional 14% reduction in ovulation efficiency as compared to vehicle-treated plg(-/-) mice. Our data therefore suggest that although MMPs may play a role in degradation of the follicular wall, they may not be obligatory for ovulation. In contrast to previous studies on tissue remodeling during wound heating and placental development, we have demonstrated that there is no obvious functional overlap or synergy between the PA and MMP systems, which has previously been thought to be essential for the ovulatory process.

Place, publisher, year, edition, pages
New York: Academic P. , 2006. Vol. 295, no 2, 615-622 p.
Keyword [en]
Animals, Dipeptides/*pharmacology/therapeutic use, Enzyme Inhibitors/pharmacology/therapeutic use, Female, Matrix Metalloproteinases/antagonists & inhibitors/*physiology, Mice, Mice; Knockout, Ovarian Follicle/enzymology/metabolism/ultrastructure, Ovulation/*drug effects, Plasminogen/*deficiency, Plasminogen Activators/physiology
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:umu:diva-6329DOI: 10.1016/j.ydbio.2006.03.046PubMedID: 16712832OAI: oai:DiVA.org:umu-6329DiVA: diva2:145998
Available from: 2007-12-09 Created: 2007-12-09 Last updated: 2014-03-11Bibliographically approved
In thesis
1. The roles of the plasminogen activator and matrix metalloproteinase systems in ovulation and corpus luteum formation
Open this publication in new window or tab >>The roles of the plasminogen activator and matrix metalloproteinase systems in ovulation and corpus luteum formation
2004 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Proteases of the plasminogen activator (PA) and the matrix metalloproteinase (MMP) enzyme systems are expressed in the ovulatory follicle and in the developing corpus luteum (CL). However, the functional role of these extracellular degrading protease systems in the ovulatory and CL development processes remains elusive. The first aim of this thesis was to develop a mouse model to study gonadotropin-induced CL formation. The second aim was to study the involvement of the PA and the MMP systems in gonadotropin-induced ovulation, and in CL formation and function.

A mouse model for gonadotropin-induced CL formation was developed in order to control the timing of CL formation. In this model, immature mice were induced to ovulate by administrating gonadotropins and the endogenous prolactin surges were mimicked by administration of prolactin twice daily from day 2 of CL development. We observed that steroidogenic acute regulatory protein (StAR) mRNA was highly expressed at days 3 and day 6 of CL development and the levels remained high until late stages of CL regression.

Since mice lacking plasminogen (plg-/-) only have a 14% reduction of ovulation efficiency, our hypothesis was that the MMP system could compensate for the loss of plasminogen. When administrating the MMP-inhibitor galardin to gonadotropin-primed ovulating mice, we found that wild-type mice (plg+/+ and C67BL/J6) and heterozygous mice (plg+/-) had an 18-20% reduction in ovulation efficiency as compared to untreated mice.

Two models for CL formation, the adult pseudopregnant (psp) mouse model and a model whereby immature gonadotropin-primed mice were treated with prolactin, were used to study the formation and function of the CL in plg-/- mice treated with galardin. At day 3 of CL development, we found no alterations other than a slightly lower number of CL in plg-/- mice. This is most likely a secondary effect of the lower ovulation efficiency found in these mice. On the other hand, we found a 54% reduction in serum progesterone levels in plg-/- mice and a 37% reduction in the plg+/- mice as compared to wild type mice. At day 6 of CL development we saw a 45 % reduction of serum progesterone level in the plg-/- mice and a 22 % reduction in the plg+/- mice. A similar trend was observed at day 3 of CL development in immature gonadotropinprimed mice treated with prolactin. Galardin treatment did not alter the results significantly and the CLs were healthy and viable in these mice.

In conclusion, our data suggest that both plasminogen and MMPs, alone or in combination, are dispensable for ovulation and for the formation of a viable CL under the conditions used in this study. The reduced serum progesterone levels observed in the plg-/- mice did not appear to be a result of defective CL formation. Instead, plasmin may have a novel role in the maintenance of luteal function. StAR expression may also be a good marker for CL development and regression in mice.

Publisher
45 p.
Keyword
ovary, ovulation, corpus luteum, plasminogen, PA, MMP, mouse
Identifiers
urn:nbn:se:umu:diva-448 (URN)91-7305-744-6 (ISBN)
Available from: 2005-02-14 Created: 2005-02-14 Last updated: 2014-03-11Bibliographically approved

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Liu, KuiWahlberg, PatrikHägglund, Anna-CarinBodén, IdaNy, Tor

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Liu, KuiWahlberg, PatrikLeonardsson, GöranHägglund, Anna-CarinNy, AnneliiBodén, IdaWibom, CarinLund, Leif RNy, Tor
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