Adaptation of uterine artery thick- and thin-filament regulatory pathways to pregnancy

Abstract

Little is known about the adaptation of uterine artery smooth muscle contractile mechanisms to pregnancy. The present study tested the hypothesis that pregnancy differentially regulates thick- and thin-filament regulatory pathways in uterine arteries. Isometric tension, intracellular free Ca2+concentration, and phosphorylation of 20-kDa myosin light chain (MLC20) were measured simultaneously in uterine arteries isolated from nonpregnant and near-term (140 days gestation) pregnant sheep. Phenylephrine-mediated intracellular free Ca2+concentration, MLC20phosphorylation, and contraction tension were significantly increased in uterine arteries of pregnant compared with nonpregnant animals. In contrast, phenylephrine-mediated Ca2+sensitivity of MLC20phosphorylation was decreased in the uterine arteries of pregnant sheep. Simultaneous measurement of phenylephrine-stimulated tension and MLC20phosphorylation in the same tissue indicated a decrease in MLC20phosphorylation-independent contractions in the uterine arteries of pregnant sheep. In addition, activation of PKC produced significantly lower sustained contractions in uterine arteries of pregnant compared with nonpregnant animals in the absence of changes in MLC20phosphorylation levels in either vessels. In uterine arteries of nonpregnant sheep, the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase inhibitor PD-098059 significantly increased phenylephrine-mediated, MLC20phosphorylation-independent contractions. The results suggest that in uterine arteries, pregnancy upregulates α1-adrenoceptor-mediated Ca2+mobilization and MLC20phosphorylation. In contrast, pregnancy downregulates the Ca2+sensitivity of myofilaments, which is mediated by both thick- and thin-filament pathways.