Reorganization of Myofilament Proteins and Decreased cGMP-Dependent Protein Kinase in the Human Uterus during Pregnancy

Abstract

Excessive or premature contractions of uterine smooth muscle may contribute to preterm labor. Contractile stimuli induce myosin and actin filament interactions through calcium-dependent myosin phosphorylation. The mechanisms that maintain myometrial quiescence until term are not well established, but may include control of calcium levels by nitric oxide and cGMP signaling and thin filament (caldesmon and calponin) regulation. Previously, we reported that myometrial tissues from pregnant rats are not responsive to cGMP due to decreases in cGMP-dependent protein kinase. Considering the well documented differences in the endocrinology of parturition among species, this study was conducted to test the hypothesis that the levels and subcellular distribution of caldesmon, calponin, and cGMP-dependent protein kinase are regulated with the hormonal milieu of human pregnancy. Whereas cGMP-dependent protein kinase was significantly reduced in the human uterus during pregnancy, caldesmon expression was significantly increased, and both caldesmon and calponin were redistributed to a readily extractable subcellular pool. These data suggest that cGMP-dependent protein kinase does not mediate gestational quiescence. Redistribution of thin filament-associated proteins, however, may alter uterine smooth muscle tone or the cytoskeletal framework of myocytes to maintain gestation despite the substantial distention that accompanies all intrauterine pregnancies.

Expression of scaffolding, signalling and contractile-filament proteins in human myometria: effects of pregnancy and labour

“…This is consistent with that previously reported for both human and rat myometrium [22,27,32]. h-Caldesmon is a thin filament-associated protein that inhibits actomyosin MgATPase activity [33].…”

“…There is an emerging body of evidence suggesting that human pregnancy, and labour onset, is associated with translational changes in many molecules whose main influence is to limit uterine activity [22,23,[34][35][36]. As ROKα and MLC 20 are key proteins implicated in smooth muscle contractile activation, their decreased expression with pregnancy reported here, coupled with an enhanced expression of h-caldesmon, may also contribute to this adaptive situation before parturition.…”

“…Several studies have assessed in human myometrium the transcriptional or translational changes occurring in expression of molecules that influence uterine quiescence [22][23][24]. In contrast, there is far less comparative information on the effect of pregnancy and labour on myometrial expression of proteins implicated in signalling pathways leading to direct contractile activation; that which is available for individual proteins is often contradictory [25,26].…”

Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition

“…Others, including calponin and h-caldesmon, modulate the actomyosin complex (13,14). Previous studies have shown that expression levels of contractile apparatus proteins increase with pregnancy (15)(16)(17).…”

The Assessment of a Selective Inhibition of Potassium Channels and Guanylate Cyclase in the Relaxation Induced by Exogenous Nitric Oxide in the Human Nonpregnant Myometrium

“…One postulated mechanism is that NO increases cGMP and relaxes smooth muscles via the inhibition of myosin light chain phosphorylation (Buxton, 2008;Cornwell et al, 2001). Another possible mechanism is that increased cGMP levels lead to hyperpolarisation of the cellular membranes ( (Khan et al, 2009;Zygmunt and Hogestatt, 1996) resulting in smooth muscle relaxation.…”