Lysyl Oxidases are Necessary for Myometrial Contractility and On-Time Parturition in Mice

Abstract

ABSTRACTThe extracellular matrix (ECM) plays a pivotal role in the maintenance of tissue mechanical homeostasis. Collagens and elastic fibers are the most predominant fibrous ECM proteins providing tissue mechanical function through covalent cross-linking which is mediated by the lysyl oxidase family of enzymes. In this study, the function of lysyl oxidases in maintaining the integrity of the extracellular matrix in the myometrium and its impact on parturition-timing was investigated. Gene and protein expression analyses demonstrate that a sub-set of the lysyl oxidase family of enzymes are highly induced in pregnant myometrium. Inhibition of the activity of the lysyl oxidase family of enzymes through β-aminopropionitrile (BAPN) delays parturition in mice, in part, due to myometrial dysfunction. In BAPN treated mice, the expression of genes encoding contraction associated proteins such as connexin 43, oxytocin receptor and prostaglandin synthase 2 is significantly reduced in the myometrium compared to the untreated control mice. Proteomic analysis revealed that the composition of the ECM is altered in response to BAPN treatment which demonstrates that the inhibition of the activity of lysyl oxidases disrupted the integrity of the myometrial ECM. Our findings demonstrate that the lysyl oxidases-mediated ECM function is necessary for the myometrium to transition from a quiescent to a contractile phenotype at term for on-time parturition.