Pregnancy

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

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 - PCNA protein expression and BrdU incorporation were studied. Myocyte hypertrophy was assessed by measuring the protein:DNA ratio. The expression levels of anti-apoptotic regulatory proteins (BCL2 and BCL2L1) and enzymes involved in apoptosis (caspase 3, 6, 7, 9, 10, known as CASP3- CASP10) were assessed by immunoblotting throughout gestation and post-partum. Myometrial cell apoptosis was determined by TUNEL staining and DNA fragmentation assays. BrdU incorporation and PCNA labeling were elevated in early pregnant myometrium and decreased dramatically after midgestation with a simultaneous increase in cellular hypertrophy. BCL2 levels were high in early gestation followed by significantly elevated BCL2L1 levels at midgestation. The expression of CASP10 in myometrial samples declined from a high non-pregnant level to a complete loss at early gestation. The cleaved forms of caspase (CC)-3,-6,-7,-9 and poly(ADP- ribose)polymerase-1 (ADPRT) were undetectable in the myometrial samples at early or late gestation but transiently elevated at midgestation. Immunohistochemical staining of CC-3 confirmed the activation of the caspase cascade though TUNEL-positive staining or the increase in DNA fragmentation were not detected. Collectively there were two distinct phases of myometrial growth: i) myocyte hyperplasia associated with increase in anti-apoptotic proteins in the first half and ii) cellular hypertrophy in the second part of gestation; the transition between phases was associated with transient activation of the caspase cascade that triggered the differentiation of uterine smooth muscle.

Key words: Pregnancy • Apoptosis • Uterus

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