Regulation of stanniocalcin‐1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia

Abstract

Naila Abid, Joan Embola and Zoe Tryfonos contributed equally to this study.Abbreviations: 8 Br-cAMP, 8-Bromo adenosine-3', 5'-cyclic monophosphate; BSA, bovine serum albumin; cAMP, adenosine-3', 5'-cyclic monophosphate; DAB, 3,3′-diaminobenzidine; DP44mT, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone; Epac, exchange proteins directly activated by cAMP; FCS, fetal calf serum; GSK-3β, glycogen synthase kinase-3β; hCG, human chorionic gonadotrophin; HIF, hypoxia-Inducible factor; HRE, hypoxia response element; IGF, insulin-like growth factor; IGFBP4, insulin-like growth factor binding protein; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; NDRG-1, N-myc downstream-regulated gene 1; NHS, National Health Service; PAPP-A, pregnancy-associated plasma protein-A; PBS, phosphate-buffered saline; PBST, phosphate-buffered saline with tween; PI 3 -Kinase, phosphatidylinositol-3 kinase; PKA, protein kinase A; SGK-1, serum and glucocorticoid-induced kinase-1; STC-1, stanniocalcin-1; TBS, tris-buffered saline; TBST, tris-buffered saline with tween. AbstractStanniocalcin-1 (STC-1) is a multi-functional glycosylated peptide present in the plasma of healthy women postpartum and increased further in pregnancies complicated by preeclampsia. Although the STC-1 gene is expressed by the placenta what regulates its secretion and from which cells at the feto-maternal interface is unknown.Here, we demonstrate for the first time that the syncytiotrophoblast and cytotrophoblast are a major site of STC-1 protein expression in first trimester placental tissue. Further, in response to low oxygen, first trimester chorionic villous tissue from pregnancies at increased risk of developing preeclampsia secreted significantly more STC-1 than normal tissue under the same conditions. Using the human trophoblast cell line BeWo we have shown that low oxygen increased the secretion of STC-1 but it required co-stimulation with the Adenosine-3', 5'-cyclic monophosphate (cAMP) analogue, 8-Bromo adenosine-3', 5'-cyclic monophosphate cAMP to reach significance. Inhibition of Hypoxia inducible factor 2α (HIF-2α) and the Phosphatidylinositol-3 kinase (PI 3 -Kinase)/AKT/Serum and glucocorticoid-induced kinase-1(SGK-1) pathway resulted in significant inhibition of STC-1 secretion. As both low oxygen and cAMP are known to play a central role in placental function, their regulation of STC-1 points to a potentially important role in the maintenance of a normal healthy pregnancy and we would hypothesize that it may act to protect against prolonged placental hypoxia seen in preeclampsia. K E Y W O R D Sfirst trimester, hypoxia, placenta, stanniocalcin-1, trophoblasts

Ghrelin promotes angiogenesis by activating the Jagged1/Notch2/VEGF pathway in preeclampsia

“…The earlier the onset of gestational age, the more serious the outcome of the disease. There are many studies of PE, [2][3][4] but its etiology and pathogenesis are far complexity and diversity. EOPE is considered to be associated with placental ischemia/ hypoxia, as a result of insufficient trophoblast invasion and impaired uterine spiral artery remodeling, 5 while LOPE is considered to be the result of villous overcrowding at term, leading to limited gaseous exchange and nutrient supply which culminates in placental oxidative stress.…”

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in gestational diabetes mellitus

“…CEBPB (CCAAT enhancer binding protein beta) [38], ACSL4 [39], MBD2 [40], ULK1 [41], NUCB2 [42], TWIST1 [43], HOOK2 [44], CLDN7 [45], TBK1 [46], YIPF6 [47], TFRC (transferrin receptor) [48], ENPP2 [49], SLIT2 [50], MFGE8 [51], FAT1 [52], GPC4 [53], COL6A3 [54], EGFL6 [55], AOC3 [56], CCN2 [57], LYVE1 [58], RARA (retinoic acid receptor alpha) [59], COL18A1 [60], THY1 [61], CD36 [62], PEMT (phosphatidylethanolamine N-methyltransferase) [63], AIF1L [64], OXTR (oxytocin receptor) [65], LMNA (lamin A/C) [66], CXCL14 [67], DKK3 [68], ANGPTL2 [69] and CMTM7 [70] were reported to be associated with obesity, but these genes might be linked with progression of GDM. AHR (aryl hydrocarbon receptor) [71], STS (steroid sulfatase) [72], PLAC1 [73], CYP11A1 [74], PSG11 [75], STAT5B [76], TLR3 [77], FOLR1 [78], HSPB1 [79], HSP90AA1 [80], ANXA4 [81], ATF3 [82], DAPK1 [83], ENTPD1 [84], ABL1 [85], VSIG4 [86], CD99 [87], VWF (von Willebrand factor) [88], PODXL (podocalyxin like) [89], PDPN (podoplanin) [90], RND3 [91], VCAN (versican) [92], AXL (AXL receptor tyrosine kinase) [93], PIEZO1 [94], GAS6 [93], LAMA4 [95], CAV1 [96], DLL1 [97], CD44 [98], CD81 [99], SMAD3 [100], NES (nestin) [101], DCN (decorin) [102], AGTR1 [103], SLIT3 [104], B2M [105], STAT3 [106], STC1 [107] and ADAMTS1 [108] were shown to participate in facilitating the preeclampsia. Majchrzak-Celiń ka et al [109] ...…”

Stanniocalcin-1 in the female reproductive system and pregnancy

“…It is possible that these SNPs explain the observed variation in placental STC-1 gene expression levels between normal and complicated pregnancies, but this requires further study ( Juhanson et al , 2016 ). Although the precise role of placental STC-1 in pregnancy has yet to be elucidated, current findings in the field suggest that it plays a role in maintaining a healthy pregnancy, but may also be implicated in the pathology of pregnancy complications ( Abid et al , 2020 ).…”

“…In addition, numerous studies have highlighted the role of STC-1 in the physiology and pathophysiology of the female reproductive system. These studies have outlined the wide expression of STC-1 amongst female reproductive tissues including the uterus ( Stasko et al , 2001 ; Xiao et al , 2006 ; Allegra et al , 2009 ), placenta ( Uusküla et al , 2012 ; Juhanson et al , 2016 ; Abid et al , 2020 ), and the developing maternal vasculature in early pregnancy ( Wallace et al , 2013 ). Amongst all female reproductive tissues, the greatest expression is seen in the ovary ( Varghese et al , 1998 ; Deol et al , 2000 ).…”