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BOR - Papers in Press, published online ahead of print March 12, 2008.
Biol Reprod 2008, 10.1095/biolreprod.107.065490
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Submitted September 10, 2007
Returned for revision October 2, 2007
Accepted January 31, 2008

Mechanisms of Hormone Action


Inhibition of Rat Oocyte Maturation and Ovulation by Nitric Oxide: Mechanism of Action

Sagit Sela-Abramovich , Dalia Galiani , Nava Nevo , and Nava Dekel *

* To whom correspondence should be addressed. E-mail: nava.dekel{at}weizmann.ac.il.

Abstract
Established gap junctional communication (GJC) in the ovarian follicle is essential for maintaining the oocytes in meiotic arrest. Alternatively, LH-induced reinitiation of meiosis is subsequent to breakdown of GJC. It was recently reported that nitric oxide (NO) inhibits maturation in rat follicle-enclosed oocytes and elevates GJC in cultured mesangial cells. Taking these observations into account, we hypothesized that NO prevents reinitiation of meiosis by antagonizing the effect of LH on GJC in the ovarian follicle. Indeed, we found that NO interferes with LH-induced disruption of GJC as well as with the decrease of the expression of the gap junction protein, GJA1 (previously known as CONNEXIN43). We also demonstrated that NO prevents LH-induced mitogen activated proteins kinase (MAPK) 1 and 2 activation and inhibits cumulus expansion. Along this line, incubation of ovarian follicles with an inhibitor of soluble guanylate cyclase, that is a downstream NO effector, induced on its own oocyte maturation as well as cumulus expansion. Unlike previous studies, we show herein that elevation of NO resulted in inhibition of ovulation. We conclude that the mechanism by which NO inhibits LH-induced oocyte maturation possibly involves a negative effect on MAPK-activation and in turn, interference with interruption of GJC. This action of NO in the ovarian follicle is apparently mediated by cGMP. In addition, the negative effect of NO on ovulation may be subsequent to its inhibitory effect on cumulus expansion. Together, this study suggests that the preovulatory decrease in NO concentrations is a prerequisite for the ovarian response to LH.

Key words: Follicle • Luteinizing hormone • Nitric oxide • Ovulation • Gap junction


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R. P. Norris, M. Freudzon, L. M. Mehlmann, A. E. Cowan, A. M. Simon, D. L. Paul, P. D. Lampe, and L. A. Jaffe
Luteinizing hormone causes MAP kinase-dependent phosphorylation and closure of connexin 43 gap junctions in mouse ovarian follicles: one of two paths to meiotic resumption
Development, October 1, 2008; 135(19): 3229 - 3238.
[Abstract] [Full Text] [PDF]




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