Abstract
Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, we assessed wild-type, biglycan, decorin and double knockout pregnancies for timing of birth and uterine function. Uteri were harvested at embryonic days 12, 15 and 18. Nonpregnant uterine samples of the same genotypes were assessed for tissue failure rate and spontaneous and oxytocin-induced contractility. We discovered that biglycan/decorin mixed double-knockout dams displayed dystocia, were at increased risk of delayed labor onset, and showed increased tissue failure in a predominantly decorin-dependent manner. In vitro spontaneous uterine contractile amplitude and oxytocin-induced contractile force were decreased in all biglycan and decorin knockout genotypes compared to wild-type. Notably, we found no significant compensation between biglycan and decorin using quantitative real time PCR or immunohistochemistry. We conclude that the biglycan/decorin mixed double knockout mouse is a model of dystocia and delayed labor onset. Moreover, decorin is necessary for uterine function in a dose-dependent manner, while biglycan exhibits partial compensatory mechanisms in vivo. Thus, this model is poised for use as a model for testing novel targets for preventive or therapeutic manipulation of uterine dysfunction.
Highlights
The rate of birth by Cesarean section has been rising steadily in the United States despite the Healthy People 2020 goal of decreasing Cesarean births
Mice First, we evaluated the parturition characteristics of the following females compared to the wild-type (Bgn+/+Dcn+/+) (Figure 1): homozygous biglycan knockout and homozygous decorin knockout mice (Bgn2/2Dcn+/+ and Bgn+/+Dcn2/2); the mixed double knockouts: biglycan heterozygous/decorin heterozygous knockout (Bgn+/2Dcn+/2), biglycan heterozygous/decorin homozygous knockout (Bgn+/2Dcn2/2), biglycan homozygous/decorin heterozygous knockout (Bgn2/2Dcn+/2); and the homozygous double knockout: (Bgn2/2Dcn2/2)
We present a novel model of uterine dysfunction leading to adverse gestational outcomes via dystocia and delayed labor onset
Summary
The rate of birth by Cesarean section has been rising steadily in the United States despite the Healthy People 2020 goal of decreasing Cesarean births It has increased by 60% since 1996 to a rate of 32% of all births in 2009 [1]. The uterus is dormant during gestation to avoid preterm birth, transitions to active contractions when expulsion of the fetus is necessary. These processes are modulated by neuronal, hormonal, metabolic and mechanical factors [3]. A variety of mechanisms have been implicated in the pathogenesis of uterine dysfunction, or dystocia These include increasing maternal age [4], stress and obesity [5]. Mice with mutations of Atp11c have dystocia [6], while overexpression of small conductance calcium-activated K channel isoform 3 leads to inefficient uterine contractility [7]
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