Skip to main content

Advertisement

SpringerLink
Log in

A role for GPR55 in human placental venous endothelial cells

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Endocannabinoids and their G protein-coupled receptors have been suggested to play a key role in human pregnancy, by regulating important aspects such as implantation, decidualization, placentation and labor. G protein-coupled receptor 55 (GPR55) was previously postulated to be another cannabinoid receptor, since specific cannabinoids were shown to act independently of the classical cannabinoid receptors CB1 or CB2. Current knowledge about GPR55 expression and function in human placenta is very limited and motivated us to evaluate human placental GPR55 expression in relation to other human peripheral tissues and to analyze spatiotemporal GPR55 expression in human placenta. Gene expression analysis revealed low GPR55 levels in human placenta, when compared to spleen and lung, the organs showing highest GPR55 expression. Moreover, expression analysis showed 5.8 fold increased placental GPR55 expression at term compared to first trimester. Immunohistochemistry located GPR55 solely at the fetal endothelium of first trimester and term placentas. qPCR and immunocytochemistry consistently confirmed GPR55 expression in isolated primary placental arterial and venous endothelial cells. Incubation with L-α-lysophosphatidylinositol (LPI), the specific and functional ligand for GPR55, at a concentration of 1 µM, significantly enhanced migration of venous, but not arterial endothelial cells. LPI-enhanced migration was inhibited by the GPR55 antagonist O-1918, suggesting a role of the LPI-GPR55 axis in placental venous endothelium function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • AlSuleimani YM, Hiley CR (2015) The GPR55 agonist lysophosphatidylinositol mediates vasorelaxation of the rat mesenteric resistance artery and induces calcium release in rat mesenteric artery endothelial cells. Br J Pharmacol

  • Baker D, Pryce G, Davies WL, Hiley CR (2006) In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol Sci 27:1–4

    Article  CAS  PubMed  Google Scholar 

  • Bouskila J, Javadi P, Casanova C, Ptito M, Bouchard JF (2013) Rod photoreceptors express GPR55 in the adult vervet monkey retina. PLoS ONE 8:e81080

    Article  PubMed Central  PubMed  Google Scholar 

  • Brown AJ (2007) Novel cannabinoid receptors. Br J Pharmacol 152:567–575

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chan HW, McKirdy NC, Peiris HN, Rice GE, Mitchell MD (2013) The role of endocannabinoids in pregnancy. Reproduction 146:R101–R109

    Article  CAS  PubMed  Google Scholar 

  • Costa MA, Fonseca BM, Teixeira NA, Correia-da-Silva G (2015) The endocannabinoid anandamide induces apoptosis in cytotrophoblast cells: involvement of both mitochondrial and death receptor pathways. Placenta 36:69–76

    Article  CAS  PubMed  Google Scholar 

  • Di Francesco A, Falconi A, Di Germanio C, Micioni Di Bonaventura MV, Costa A, Caramuta S, Del Carlo M, Compagnone D, Dainese E, Cifani C, Maccarrone M, D’Addario C (2014) Extravirgin olive oil up-regulates CB tumor suppressor gene in human colon cancer cells and in rat colon via epigenetic mechanisms. J Nutr Biochem

  • Dudzik D, Zorawski M, Skotnicki M, Zarzycki W, Kozlowska G, Bibik-Malinowska K, Vallejo M, Garcia A, Barbas C, Ramos MP (2014) Metabolic fingerprint of gestational diabetes mellitus. J Proteomics 103:57–71

    Article  CAS  PubMed  Google Scholar 

  • Fonseca BM, Teixeira NA, Almada M, Taylor AH, Konje JC, Correia-da-Silva G (2011) Modulation of the novel cannabinoid receptor-GPR55-during rat fetoplacental development. Placenta 32:462–469

    Article  CAS  PubMed  Google Scholar 

  • Fonseca BM, Correia-da-Silva G, Almada M, Costa MA, Teixeira NA (2013) The endocannabinoid system in the postimplantation period: a role during decidualization and placentation. Int J Endocrinol 2013:510540

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ford LA, Roelofs AJ, Anavi-Goffer S, Mowat L, Simpson DG, Irving AJ, Rogers MJ, Rajnicek AM, Ross RA (2010) A role for L-alpha-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells. Br J Pharmacol 160:762–771

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fugedi G, Molnar M, Rigo J, Schonleber J, Kovalszky I, Molvarec A (2014) Increased placental expression of cannabinoid receptor 1 in preeclampsia: an observational study. BMC Pregnancy Childbirth 14:395

    Article  PubMed Central  PubMed  Google Scholar 

  • Habayeb OM, Taylor AH, Bell SC, Taylor DJ, Konje JC (2008) Expression of the endocannabinoid system in human first trimester placenta and its role in trophoblast proliferation. Endocrinology 149:5052–5060

    Article  CAS  PubMed  Google Scholar 

  • Henstridge CM, Balenga NA, Ford LA, Ross RA, Waldhoer M, Irving AJ (2009) The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2 + signaling and NFAT activation. FASEB J 23:183–193

    Article  CAS  PubMed  Google Scholar 

  • Henstridge CM, Balenga NA, Kargl J, Andradas C, Brown AJ, Irving A, Sanchez C, Waldhoer M (2011) Minireview: recent developments in the physiology and pathology of the lysophosphatidylinositol-sensitive receptor GPR55. Mol Endocrinol 25:1835–1848

    Article  CAS  PubMed  Google Scholar 

  • Joo JE, Hiden U, Lassance L, Gordon L, Martino DJ, Desoye G, Saffery R (2013) Variable promoter methylation contributes to differential expression of key genes in human placenta-derived venous and arterial endothelial cells. BMC Genom 14:475–485

    Article  CAS  Google Scholar 

  • Kargl J, Brown AJ, Andersen L, Dorn G, Schicho R, Waldhoer M, Heinemann A (2013) A selective antagonist reveals a potential role of G protein-coupled receptor 55 in platelet and endothelial cell function. J Pharmacol Exp Ther 346:54–66

    Article  CAS  PubMed  Google Scholar 

  • Kaufmann P, Mayhew TM, Charnock-Jones DS (2004) Aspects of human fetoplacental vasculogenesis and angiogenesis. II. Changes during normal pregnancy. Placenta 25:114–126

    Article  CAS  PubMed  Google Scholar 

  • Kotsikorou E, Madrigal KE, Hurst DP, Sharir H, Lynch DL, Heynen-Genel S, Milan LB, Chung TD, Seltzman HH, Bai Y, Caron MG, Barak L, Abood ME, Reggio PH (2011) Identification of the GPR55 agonist binding site using a novel set of high-potency GPR55 selective ligands. Biochemistry 50:5633–5647

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lang I, Schweizer A, Hiden U, Ghaffari-Tabrizi N, Hagendorfer G, Bilban M, Pabst MA, Korgun ET, Dohr G, Desoye G (2008) Human fetal placental endothelial cells have a mature arterial and a juvenile venous phenotype with adipogenic and osteogenic differentiation potential. Differentiation 76:1031–1043

    Article  CAS  PubMed  Google Scholar 

  • Li K, Feng JY, Li YY, Yuece B, Lin XH, Yu LY, Li YN, Feng YJ, Storr M (2013) Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice. Pancreas 42:123–129

    Article  CAS  PubMed  Google Scholar 

  • Lin XH, Yuece B, Li YY, Feng YJ, Feng JY, Yu LY, Li K, Li YN, Storr M (2011) A novel CB receptor GPR55 and its ligands are involved in regulation of gut movement in rodents. Neurogastroenterol Motil 23:862–871

    Article  CAS  PubMed  Google Scholar 

  • Liu B, Song S, Jones PM, Persaud SJ (2015) GPR55: from orphan to metabolic regulator? Pharmacol Ther 145C:35–42

    Article  Google Scholar 

  • Marczylo TH, Lam PM, Amoako AA, Konje JC (2010) Anandamide levels in human female reproductive tissues: solid-phase extraction and measurement by ultraperformance liquid chromatography tandem mass spectrometry. Anal Biochem 400:155–162

    Article  CAS  PubMed  Google Scholar 

  • Moghadam KK, Kessler CA, Schroeder JK, Buckley AR, Brar AK, Handwerger S (2005) Cannabinoid receptor I activation markedly inhibits human decidualization. Mol Cell Endocrinol 229:65–74

    Article  PubMed  Google Scholar 

  • Moreno-Navarrete JM, Catalan V, Whyte L, Diaz-Arteaga A, Vazquez-Martinez R, Rotellar F, Guzman R, Gomez-Ambrosi J, Pulido MR, Russell WR, Imbernon M, Ross RA, Malagon MM, Dieguez C, Fernandez-Real JM, Fruhbeck G, Nogueiras R (2012) The L-alpha-lysophosphatidylinositol/GPR55 system and its potential role in human obesity. Diabetes 61:281–291

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T (2007) Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun 362:928–934

    Article  CAS  PubMed  Google Scholar 

  • Pineiro R, Maffucci T, Falasca M (2011) The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation. Oncogene 30:142–152

    Article  CAS  PubMed  Google Scholar 

  • Ruban EL, Ferro R, Arifin SA, Falasca M (2014) Lysophosphatidylinositol: a novel link between ABC transporters and G-protein-coupled receptors. Biochem Soc Trans 42:1372–1377

    Article  CAS  PubMed  Google Scholar 

  • Sanger GJ (2007) Endocannabinoids and the gastrointestinal tract: what are the key questions? Br J Pharmacol 152:663–670

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, George SR, O’Dowd BF (1999) Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brain Res Mol Brain Res 64:193–198

    Article  CAS  PubMed  Google Scholar 

  • Sharir H, Console-Bram L, Mundy C, Popoff SN, Kapur A, Abood ME (2012) The endocannabinoids anandamide and virodhamine modulate the activity of the candidate cannabinoid receptor GPR55. J Neuroimmune Pharmacol 7:856–865

    Article  PubMed Central  PubMed  Google Scholar 

  • Sutphen R, Xu Y, Wilbanks GD, Fiorica J, Grendys EC, LaPolla JP, Arango H, Hoffman MS, Martino M, Wakeley K, Griffin D, Blanco RW, Cantor AB, Xiao YJ, Krischer JP (2004) Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomarkers Prev 13:1185–1191

    CAS  PubMed  Google Scholar 

  • Taylor AH, Finney M, Lam PM, Konje JC (2011) Modulation of the endocannabinoid system in viable and non-viable first trimester pregnancies by pregnancy-related hormones. Reprod Biol Endocrinol 9:152–169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Waldeck-Weiermair M, Zoratti C, Osibow K, Balenga N, Goessnitzer E, Waldhoer M, Malli R, Graier WF (2008) Integrin clustering enables anandamide-induced Ca2 + signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression. J Cell Sci 121:1704–1717

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, Ross RA, Rogers MJ (2009) The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A 106:16511–16516

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wilhelmsen K, Khakpour S, Tran A, Sheehan K, Schumacher M, Xu F, Hellman J (2014) The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells. J Biol Chem 289:13079–13100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang X, Maor Y, Wang JF, Kunos G, Groopman JE (2010) Endocannabinoid-like N-arachidonoyl serine is a novel pro-angiogenic mediator. Br J Pharmacol 160:1583–1594

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Bettina Amtmann and Petra Wagner for recruiting placental tissue samples for this study. Moreover, the authors are indebted to Heidi Miedl and Monika Sundl for their cell isolation, cell culture work and assistance with immunohistochemistry. First-trimester placental tissues were provided by Dr. Andreas Glasner. M. Gauster is supported by the Austrian Science Fund (FWF): P23859-B19.

Conflict of interest

The authors declare they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Cell Biology, Histology and Embryology, Medical University Graz, Harrachgasse 21/VII, 8010, Graz, Austria

    Julia Kremshofer, Monika Siwetz, Ingrid Lang, Berthold Huppertz & Martin Gauster

  2. Division of Neonatology, Department of Pediatrics and Adolescence Medicine, Medical University Graz, Graz, Austria

    Veronika M. Berghold

Authors
  1. Julia Kremshofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monika Siwetz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Veronika M. Berghold
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ingrid Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Berthold Huppertz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin Gauster
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Gauster.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kremshofer, J., Siwetz, M., Berghold, V.M. et al. A role for GPR55 in human placental venous endothelial cells. Histochem Cell Biol 144, 49–58 (2015). https://doi.org/10.1007/s00418-015-1321-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-015-1321-7

Keywords

Search

Navigation