Biol Reprod
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BOR - Papers in Press, published online ahead of print January 11, 2006.
Biol Reprod 2006, 10.1095/biolreprod.105.048124
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BIOLOGY OF REPRODUCTION 74, 839–849 (2006)
DOI: 10.1095/biolreprod.105.048124
© 2006 by the Society for the Study of Reproduction, Inc.

Research Article

Myometrial Apoptosis: Activation of the Caspase Cascade in the Pregnant Rat Myometrium at Midgestation1

Oksana Shynlova 3, Alexandra Oldenhof 34 , Anna Dorogin 3, Quang Xu 3, Junwu Mu 3, Natty Nashman 34 , and Stephen J. Lye 2 345  

Samuel Lunenfeld Research Institute,3 Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada Departments of Physiology4 and Obstetrics & Gynecology,5 University of Toronto, Ontario M5S 1A1, Canada

ABSTRACT

In the present study, we determined the contribution of myometrial hyperplasia, hypertrophy, and apoptosis to uterine growth during pregnancy. The changes in two endogenous markers of cell replication, proliferating cell nuclear antigen (PCNA) protein expression and bromodeoxyuridine (BrdU) incorporation, were studied. Myocyte hypertrophy was assessed by measuring the protein:DNA ratio. The expression levels of antiapoptotic regulatory proteins (BCL2 and BCL2L1) and enzymes involved in apoptosis (caspases 3, 6, 7, 9, and 10) were assessed by immunoblotting throughout gestation and postpartum. Myometrial cell apoptosis was determined by TUNEL staining and DNA fragmentation assays. Both BrdU incorporation and PCNA labeling were elevated in early pregnant myometrium and decreased dramatically after midgestation, with a simultaneous increase in cellular hypertrophy. Levels of BCL2 were high during early gestation, followed by significantly elevated levels of BCL2L1 at midgestation. The expression of caspase 10 in myometrial samples declined from a high nonpregnant level to a complete loss at early gestation. The cleaved forms of caspases (CC) 3, 6, 7, and 9, as well as poly(ADP-ribose)polymerase-1, were undetectable in the myometrial samples at early or late gestation but were transiently elevated at midgestation. Immunohistochemical staining of CC3 confirmed the activation of the caspase cascade, but TUNEL-positive staining or the increase in DNA fragmentation was not detected. Collectively, two distinct phases of myometrial growth were observed: myocyte hyperplasia associated with an increase in antiapoptotic proteins during the first half of gestation, and cellular hypertrophy during the second part of gestation. The transition between these phases was associated with transient activation of the caspase cascade that triggered the differentiation of uterine smooth muscle.

apoptosis, pregnancy, uterus

FOOTNOTES

1 Supported by a grant from the Canadian Institute of Health Research.

2 Correspondence: Stephen J. Lye, Samuel Lunenfeld Research Institute at Mount Sinai, 600 University Avenue, Suite 870, Toronto, Ontario M5G 1X5, Canada. FAX: 416 586 8740; lye{at}mshri.on.ca






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Copyright © 2006 by the Society for the Study of Reproduction.