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Serotonin Increases Human Myometrial Contractility in a Focal Adhesion Signaling Independent Manner
Abstract Number: BP-04
Abstract Type: Original Research
Background: Serotonin (5HT) is a potent uterine stimulant and vascular constrictor, but the signaling pathways for 5HT-induced uterine contractions have not been identified. Src kinase is a major regulator of focal adhesion (FA) turnover in myometrium.(1) Using microarray data confirmed by cellular biochemistry, 5HT-2a expression increases significantly in late pregnancy. Thus, 5HT might play a role in regulation of uterine contractility. Our hypothesis was to determine whether Src kinase modulates 5HT-induced contraction and whether 5HT activates FA signaling.
Methods: After informed written consent, human uterine samples were collected from term pregnant women undergoing Cesarean section. Myometrial strips were exposed to 5HT in a myobath and contractility was measured as area under curve for 10 minutes (AUC 10’). We tested the effect of PP2, a Src kinase inhibitor, on 5HT-induced contraction. Phosphorylation and activation of FA signaling molecules, FAK (focal adhesion kinase) and ERK, were assessed by Western immunoblotting.
Results: 5HT significantly increased tyrosine phosphorylation of FAK (Fig. 1), as did mechanical stretch. 5HT-induced phosphorylation of ERK1/2 was also observed. FAK and ERK activation are well known to be associated with FA signaling. (2) Furthermore, 10-6M 5HT markedly augmented spontaneous contraction and significantly increased contractility (AUC 10’ baseline 12.4±1.4 vs. 223.9±98.7, n=6, p=0.028). Stretch of smooth muscle also induced contraction, to a greater extent compared to 5HT (AUC 10’ 908.9±144.5). Pretreatment of PP2 significantly suppressed 5HT-induced ERK serine phosphorylation, but failed to prevent FAK tyrosine phosphorylation, indicating that FAK is an upstream kinase positioned to ERK in FA signaling pathway. More importantly, Src inhibitor had no inhibition on 5HT-induced contraction (AUC 10’ 154±25.9 vs. 223.9±98.7, p=0.75). The data suggest that 5HT could activate FA signaling, but acts predominantly via a FA signaling-independent pathways.
Conclusion: We demonstrated that 5HT regulates uterine contractility on isolated uterine strips in a FA signaling-independent manner. Also, inhibition of ERK phosphorylation by PP2 fails to prevent 5HT-induced contractions. These data point to the possibility that serotonin is a potent uterotonic agent that may play a key role in uterine atony and postpartum hemorrhage.
1. Li Y, et al. PLoS ONE 2009; 4:e7489
2. Min J, et al. J Cell Physiol. 2012; 227:3585