Elevated plasma levels of lysophosphatidic acid and aberrant expression of lysophosphatidic acid receptors in adenomyosis

Abstract

BackgroundGiven the important roles of the receptor-mediated lysophosphatidic acid (LPA) signaling in both reproductive tract function and gynecological cancers, it will be informative to investigate the potential role of LPA in the development of adenomyosis. The objective of this study was to evaluate the levels of LPA in plasma and the expression of six LPA receptors in the endometrial tissue collected from women with and without adenomyosis.MethodsPlasma and endometrial tissue samples were collected form women with and without adenomyosis. The levels of LPA in plasma were determined by using high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Immunohistochemistry was performed to evaluate the expression of six LPA receptors (LPA1–6) in endometrial tissue samples. The effects of LPA on IL-8 production, VEGF production and cell proliferation in human endometrial stromal cells (ESCs) were also assessed.ResultsLPA1 staining was localized to the cytoplasm, membrances of the epithelial cells of the endometrial glands, and there was little staining in the stromal cells. LPA2–5 staining were localized to the nuclei of stromal and glandular cells. Plasma levels of LPA were increased in adenomyosis. LPA1, LPA4 and LPA5 immunoreactivity were significantly higher in the adenomyosis group than in the control group, while LPA2 and LPA3 immunoreactivity were significantly lower in the adenomyosis group than in the control group. LPA6 was undetectable in the endometria. LPA induced the release of IL-8 from ESCs but did not affect cell proliferation and VEGF production.ConclusionThese results indicate that elevated plasma levels of LPA and aberrant expression of LPA receptors in the endometria may be associated with the development of adenomyosis.

Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review

“…The lack of information poses risk of selection bias of study participants. Only a limited number of studies controlled for possible confounders, such as comorbidity, menstrual phase, age or parity (Liu et al ., 2016; Yang et al ., 2017; Cai et al ., 2018; Liu et al ., 2018). The preclinical animal studies on anti-angiogenic therapy often lacked clear reasoning why a specific animal model was chosen, a clear description of how the disease was defined and full disclosure on the type of anesthesia/euthanasia, description of general well-being and relevant physiological parameters of the animals.…”

“…Immunoreactivity of α-SMA, TGF-β1 and vimentin (only ectopic) (Liu et al ., 2016; Cai et al ., 2018), MMP 2–9 (Li et al ., 2006; Tokyol et al ., 2009), TF (Liu et al ., 2011; Li et al ., 2013), DJ-1/ p -mTOR (Guo et al ., 2015), follistatin, myostatin (Carrarelli et al ., 2015), LPA1,4–5 (Yang et al ., 2017), pSTAT3 (Wang et al ., 2016), IL-6 and IL-10 (only eutopic) (Zhihong et al ., 2016) and IL-22 (Wang et al ., 2014) was reported in both glandular epithelial cells and stromal cells. Tissue expression of E-cadherin, eIF3e (Liu et al ., 2016; Cai et al ., 2018), SLIT (Nie et al ., 2011) and GRIM-19 (Wang et al ., 2016) was only reported in epithelial cells, while NF-κB (p50, p65) (Li et al ., 2013; Nie et al ., 2009) and CD41 (Liu et al ., 2016) expression was only reported in the stroma.…”

“…Differences between the two menstrual phases were not studied for α-SMA, TGF-β1, platelet aggregation (CD41), vimentin, E-cadherin, eIF3e (Liu et al ., 2016; Cai et al ., 2018), NF-κB (Nie et al ., 2009; Li et al ., 2013) and IL-22 (Wang et al ., 2014). The samples for LPA (Yang et al ., 2017), activin A, follistatin and myostatin (Carrarelli et al ., 2015) were all collected in the proliferative phase, while the samples for IL-6 and IL-10 (Zhihong et al ., 2016) and Eng were only taken in the secretory phase (Hayrabedyan et al ., 2005).…”

“…The other angiogenic markers identified in this review, such as IL-6, IL-22, LPA (1-6), SLIT/ROBO, activin A, follistatin, myostatin and pSTAT3, stimulate endometrial stromal cells to produce VEGF (Carrarelli et al ., 2015; Rocha et al ., 2012; Wang et al ., 2014; Wang et al ., 2016) and induce autocrine activity, attraction, migration and proliferation of vascular endothelial cells (Wu et al ., 2005; Kozian et al ., 1997; Dickinson and Duncan, 2010; Wang et al ., 2003; Wang et al ., 2008; Yang et al ., 2017). However, previous studies reported no positive correlation of SLIT/ROBO with MVD (Wang et al ., 2003), and when LPA was added to a culture of endometrial stromal cells, there were no differences in the release of VEGF between cases and controls (Yang et al ., 2017). The presence of activin A was previously linked to the development of AUB and dysmenorrhea since it increased VEGF in endometriosis patients (Rocha et al ., 2012).…”

Pain syndrome in adenomyosis. Finding new pathogenesis links and non-hormonal correction opportunities. Literature review

“…Серед великої кількості описаних у сучасних літературних джерелах патогенетичних ланок больового синдрому при аденоміозі слід згадати наступні: збільшення щільності нервових закінчень у ділянці ендометріоїдних гетеротопій із гіперіннервацією еутопічного ендометрія, порушення структури нервів та їхньої сенситизації поряд із дисбалансом сенсорної і симпатичної іннервації та відповідних нейротрансмітерів [5][6][7][8], локальне запалення та підвищення концентрації медіаторів болю у перитонеальній рідині. Є дані, які свідчать, що інвазивне зростання ектопічного ендометрія при аденоміозі здійснюється за активної участі протеолітичних ферментів і компонентів калікреїн-кінінової системи.…”