Abstract
The smooth muscle of the uterus during pregnancy presents a unique circumstance of physiological mechanotransduction as the tissue remodels in response to stretches imposed by the growing foetus(es), yet the nature of the molecular and functional adaptations remain unresolved. We studied, in myometrium isolated from non-pregnant (NP) and pregnant mice, the active and passive length–tension curves by myography and the expression and activation by immunoblotting of focal adhesion-related proteins known in other systems to participate in mechanosensing and mechanotransduction. In situ uterine mass correlated with pup number and weight throughout pregnancy. In vitro myometrial active, and passive, length-tension curves shifted significantly to the right during pregnancy indicative of altered mechanosensitivity; at term, maximum active tension was generated following 3.94 ± 0.33-fold stretch beyond slack length compared to 1.91 ± 0.12-fold for NP mice. Moreover, mechanotransduction was altered during pregnancy as evidenced by the progressive increase in absolute force production at each optimal stretch. Pregnancy was concomitantly associated with an increased expression of the dense plaque-associated proteins FAK and paxillin, and elevated activation of FAK, paxillin, c-Src and extracellular signal-regulated kinase (ERK1/2) which reversed 1 day post-partum. Electron microscopy revealed close appositioning of neighbouring myometrial cells across a narrow extracellular cleft adjoining plasmalemmal dense plaques. Collectively, these results suggest a physiological basis of myometrial length adaptation, long known to be a property of many smooth muscles, whereupon plasmalemmal dense plaque proteins serve as molecular signalling and structural platforms contributing to functional (contractile) remodelling in response to chronic stretch.
Highlights
Mechanical forces are important regulators of cell and organ physiology
It is well known that mechanical stretch can induce uterine cell hypertrophy and hyperplasia [23,24,25,26] and here we show that pregnancy is associated with a profound shift in mechanosensitivity of myometrial contractility
This phenomenon of altered mechanosensitivity as a result of in vivo physiological circumstances resembles that observed in airway smooth muscle in vitro: pre-loading of tissues for 24 hrs at lengths less than optimal resulted in subsequent length–tension profiles that were sensitized relative to tissues preloaded at longer lengths [8]
Summary
Mechanical forces are important regulators of cell and organ physiology. Cell growth, migration and contractility [1,2,3,4] are strongly influenced by mechanical stretch in a variety of cell types, especially smooth muscle cells [5]. The sensitivity of smooth muscle to mechanical signals allows for rapid changes in muscle length and provides a physiological (and pathophysiological) mechanism by which hollow organs respond to volume changes [5,6,7] for example, in airway and vascular. C-Src interaction with FAK and/or paxillin can recruit additional signalling proteins and activate extracellular signalregulated kinase (ERK1/2) [13,14,15,16] Vol 12, No 4, 2008 complex formation that binds directly to actin and -integrins [12]. c-Src interaction with FAK and/or paxillin can recruit additional signalling proteins and activate extracellular signalregulated kinase (ERK1/2) [13,14,15,16]
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