Long Chain Polyunsaturated Fatty Acids Alter Oxytocin Signaling and Receptor Density in Cultured Pregnant Human Myometrial Smooth Muscle Cells

Abstract

Epidemiological studies and interventional clinical trials indicate that consumption of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) such as docosahexaenoic acid (DHA) lengthen gestational duration. Although the mechanisms are not well understood, prostaglandins (PG) of the 2-series are known to play a role in the initiation and progress of labor. In animal studies, modest DHA provision has been shown to reduce placental and uterine PGE2 and PGF2α, matrix metalloproteinase (MMP)-2 and MMP-9 expression, and placental collagenase activity. However, modulation of PG biosynthesis may not account for all the effects of LC n-3 PUFAs in labor. We investigated one potential PG-independent mechanism of LC PUFA action using cultured pregnant human myometrial smooth muscle cells. Our goal was to characterize the effect of LC PUFA treatment on oxytocin signaling, a potent uterotonic hormone involved in labor. The addition of 10 µM–100 µM DHA or arachidonic acid (AA) to the culture media for 48 h resulted in dose dependent enrichment of these fatty acids in membrane lipid. DHA and AA significantly inhibited phosphatidylinositol turnover and [Ca2+]i mobilization with oxytocin stimulation compared to bovine serum albumin control and equimolar oleic acid. DHA and AA significantly reduced oxytocin receptor membrane concentration without altering binding affinity or rate of receptor internalization. These findings demonstrate a role for LC n-3 PUFAs in regulation of oxytocin signaling and provide new insight into additional mechanisms pertaining to reports of dietary fish and fish oil consumption prolonging gestation.

Effect of oleic acid supplementation on prostaglandin production in maternal endometrial and fetal allantochorion cells isolated from late gestation ewes

“…Both cholesterol concentrations and localization within caveolin-1 enriched domains have previously been shown to alter OT signalling [41,42]. No evidence for this was, however, found in a study of immortalised human myometrial cells in which there were no significant differences between BSA and OA treatments with respect to changes in intracellular Ca 2+ , phosphatidylinositol turnover or oxytocin binding capacity or binding affinity following an OT challenge [11]. Using a different approach, we have recently correlated circulating NEFA concentrations in postpartum cows treated to induce differing degrees of negative energy balance as described previously [43] with microarray gene expression data in the endometrium.…”

“…Amongst these, oleic acid (OA, 18:1n-9) accounts for about 30% of the NEFAs circulating during pregnancy in women and up to 45% in sheep [8]: its concentration increases in women with gestational diabetes mellitus [9] and OA was the NEFA with the greatest increase (67%) associated with pre-eclampsia [6]. OA also constituted around 10% of the fatty acids present in amniotic fluid [10] and 30% of total membrane fatty acids in immortalised pregnant human myometrial cells [11]. Circulating NEFA concentrations including OA also rise during negative energy balance when body lipids are mobilised to supply extra energy [7].…”

Progesterone levels and days to luteolysis in mares treated with intrauterine fractionated coconut oil

“…It was hypothesized by Wilsher et al [13] in 2011 that the oil would coat the luminal epithelium of the endometrium and physically interfere with the production or release of prostaglandin from the glandular epithelium, or that the various plant oils which contain poly unsaturated fatty acids (PUFA), could have an inhibitory action on COX-1 and COX-2. In human myometrium in vitro exposure to long-chain polyunsaturated acids (n-3 PUFA) such as decosohexaneoic acid (DHA) and arachidonic acid reduces prostaglandin E2 and PGF 2-a significantly [24]. Penrod et al [25] (2013) reported on the effects of the fatty acids added to equine endometrial explant cultures that were then challenged with oxytocin.…”

Oxytocin increases inhibitory synaptic transmission and blocks development of long-term potentiation in the lateral amygdala

“…In both the periphery and the brain, OT binds to a single G protein-coupled receptor that can utilize either G q or G i proteins (Phaneuf et al 1995), and the binding of OT to OTRs activates the phospholipase C pathway that leads to the release of calcium from internal stores (Phillippe and Chien 1998). In smooth muscle cells, this leads to activation of myosin light chain kinase that initiates muscle fiber contractions (Kim et al 2012). In neurons, OTR activation increases excitability in medial amygdala (Terenzi and Ingram 2005), central amygdala (CeA) (Huber et al 2005;Terenzi and Ingram 2005), and hilar interneurons of the hippocampus (Harden and Frazier 2016).…”