Cell and Tissue Research

, Volume 362, Issue 2, pp 441–446 | Cite as

The endocannabinoid anandamide affects the synthesis of human syncytiotrophoblast-related proteins

  • M. A. Costa
  • B. M. Fonseca
  • A. Mendes
  • J. Braga
  • N. A. Teixeira
  • Georgina Correia da SilvaEmail author
Short Communication


The human syncytiotrophoblast (hST) has a major role in the production of important placental hormones. Several molecules regulate hST endocrine function but the role of endocannabinoids in this process is still unknown. Here, we report that the endocannabinoid anandamide (AEA) decreased cAMP levels, impaired human chorionic gonadotropin secretion, placental alkaline phosphatase activity and decreased aromatase mRNA levels and protein expression, through cannabinoid (CB) receptor activation. AEA also downregulated leptin and placental protein 13 transcription, though via a CB receptor-independent mechanism. All this evidence suggests AEA is a novel modulator of hormone synthesis by the syncytiotrophoblast, supporting the importance of the endocannabinoid signalling in placental function.


Anandamide Endocannabinoid signalling Placental proteins Human syncytiotrophoblast Placenta 



The authors thank Fundação para a Ciência e Tecnologia (FCT) for the post-doctoral grant of Bruno Fonseca (SFRH/BPD/72958/2010).


This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Competing interests

The authors declare that they have no competing interests.


  1. Cole LA (2012) hCG, the wonder of today’s science. Reprod Biol Endocrinol 10:24PubMedCentralCrossRefPubMedGoogle Scholar
  2. Costa MA, Fonseca BM, Keating E, Teixeira NA, Correia-da-Silva G (2014) Transient receptor potential vanilloid 1 is expressed in human cytotrophoblasts: Induction of cell apoptosis and impairment of syncytialization. Int J Biochem Cell Biol 57:177–185CrossRefPubMedGoogle Scholar
  3. Costa MA, Fonseca BM, Teixeira NA, Correia-da-Silva G (2015a) The endocannabinoid anandamide induces apoptosis in cytotrophoblast cells: involvement of both mitochondrial and death receptor pathways. Placenta 36:69–76CrossRefPubMedGoogle Scholar
  4. Costa MA, Keating E, Fonseca BM, Teixeira NA, Correia-da-Silva G (2015b) 2-Arachidonoylglycerol impairs human cytotrophoblast cells syncytialization: influence of endocannabinoid signalling in placental development. Mol Cell Endocrinol 399:386–394CrossRefPubMedGoogle Scholar
  5. Fonseca BM, Costa MA, Almada M, Correia-da-Silva G, Teixeira NA (2013) Endogenous cannabinoids revisited: a biochemistry perspective. Prostaglandins Other Lipid Mediat 102–103:13–30CrossRefPubMedGoogle Scholar
  6. Ge YC, Li JN, Ni XT, Guo CM, Wang WS, Duan T, Sun K (2011) Cross talk between cAMP and p38 MAPK pathways in the induction of leptin by hCG in human placental syncytiotrophoblasts. Reproduction 142:369–375CrossRefPubMedGoogle Scholar
  7. Gomez-Concha C, Flores-Herrera O, Olvera-Sanchez S, Espinosa-Garcia MT, Martinez F (2011) Progesterone synthesis by human placental mitochondria is sensitive to PKA inhibition by H89. Int J Biochem Cell Biol 43:1402–1411CrossRefPubMedGoogle Scholar
  8. 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 149:5052–5060CrossRefPubMedGoogle Scholar
  9. Huppertz B, Meiri H, Gizurarson S, Osol G, Sammar M (2013) Placental protein 13 (PP13): a new biological target shifting individualized risk assessment to personalized drug design combating pre-eclampsia. Hum Reprod Update 19:391–405CrossRefPubMedGoogle Scholar
  10. Keryer G, Alsat E, Tasken K, Evain-Brion D (1998) Cyclic AMP-dependent protein kinases and human trophoblast cell differentiation in vitro. J Cell Sci 111(Pt 7):995–1004PubMedGoogle Scholar
  11. Kirkegaard I, Uldbjerg N, Oxvig C (2010) Biology of pregnancy-associated plasma protein-A in relation to prenatal diagnostics: an overview. Acta Obstet Gynecol Scand 89:1118–1125CrossRefPubMedGoogle Scholar
  12. Kliman HJ, Nestler JE, Sermasi E, Sanger JM, Strauss JF 3rd (1986) Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology 118:1567–1582CrossRefPubMedGoogle Scholar
  13. Lunghi L, Ferretti ME, Medici S, Biondi C, Vesce F (2007) Control of human trophoblast function. Reprod Biol Endocrinol 5:6PubMedCentralCrossRefPubMedGoogle Scholar
  14. Maccarrone M, Bari M, Battista N, Finazzi-Agro A (2002) Estrogen stimulates arachidonoylethanolamide release from human endothelial cells and platelet activation. Blood 100:4040–4048CrossRefPubMedGoogle Scholar
  15. Malassine A, Cronier L (2002) Hormones and human trophoblast differentiation: a review. Endocrine 19:3–11CrossRefPubMedGoogle Scholar
  16. Maldonado-Mercado MG, Espinosa-Garcia MT, Gomez-Concha C, Monreal-Flores J, Martinez F (2008) Steroidogenesis in BeWo cells: role of protein kinase A and benzodiazepines. Int J Biochem Cell Biol 40:901–908CrossRefPubMedGoogle Scholar
  17. 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 400:155–162CrossRefPubMedGoogle Scholar
  18. Maymo JL, Perez Perez A, Sanchez-Margalet V, Duenas JL, Calvo JC, Varone CL (2009) Up-regulation of placental leptin by human chorionic gonadotropin. Endocrinology 150:304–313CrossRefPubMedGoogle Scholar
  19. Michael MD, Kilgore MW, Morohashi K, Simpson ER (1995) Ad4BP/SF-1 regulates cyclic AMP-induced transcription from the proximal promoter (PII) of the human aromatase P450 (CYP19) gene in the ovary. J Biol Chem 270:13561–13566CrossRefPubMedGoogle Scholar
  20. Orendi K, Gauster M, Moser G, Meiri H, Huppertz B (2010) The choriocarcinoma cell line BeWo: syncytial fusion and expression of syncytium-specific proteins. Reproduction 140:759–766CrossRefPubMedGoogle Scholar
  21. Perez-Perez A, Sanchez-Jimenez F, Maymo J, Duenas JL, Varone C, Sanchez-Margalet V (2015) Role of leptin in female reproduction. Clin Chem Lab Med 53:15–28CrossRefPubMedGoogle Scholar
  22. Rossi G, Gasperi V, Paro R, Barsacchi D, Cecconi S, Maccarrone M (2007) Follicle-stimulating hormone activates fatty acid amide hydrolase by protein kinase A and aromatase-dependent pathways in mouse primary Sertoli cells. Endocrinology 148:1431–1439CrossRefPubMedGoogle Scholar
  23. Trabucco E, Acone G, Marenna A, Pierantoni R, Cacciola G, Chioccarelli T, Mackie K, Fasano S, Colacurci N, Meccariello R, Cobellis G, Cobellis L (2009) Endocannabinoid system in first trimester placenta: low FAAH and high CB1 expression characterize spontaneous miscarriage. Placenta 30:516–522CrossRefPubMedGoogle Scholar
  24. Wang W, Li J, Ge Y, Li W, Shu Q, Guan H, Yang K, Myatt L, Sun K (2012) Cortisol induces aromatase expression in human placental syncytiotrophoblasts through the cAMP/Sp1 pathway. Endocrinology 153:2012–2022CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • M. A. Costa
    • 1
  • B. M. Fonseca
    • 2
  • A. Mendes
    • 3
  • J. Braga
    • 3
  • N. A. Teixeira
    • 2
  • Georgina Correia da Silva
    • 2
    Email author
  1. 1.Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de FarmáciaUniversidade do PortoPortoPortugal
  2. 2.UCIBIO, REQUIMTE, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de FarmáciaUniversidade do PortoPortoPortugal
  3. 3.Departamento da Mulher e da Criança, Serviço de ObstetríciaCentro Materno-Infantil do Norte- Centro Hospitalar do PortoPortoPortugal

Personalised recommendations