Abstract
The impairment of trophoblast invasion associated with preeclampsia may involve matrix metalloproteinase (MMP). Adenosine A3 receptors expression in trophoblast is upregulated in preeclampsia. This study was designed to determine if A3 receptors modulate MMP secretion in villous explants from preeclamptic pregnancies. Villous explants from normal and preeclamptic pregnancies were cultured at 20% and 3% oxygen. There were significantly increased A3 receptor and reduced MMP-2/-9 expression at low oxygen level in normal and preeclamptic explants. Interestingly, in preeclamptic explants, after high oxygen culture, the expression of MMP-2/-9 were recovered to almost same level of those in normal explants. Treatment of preeclamptic explants with A3 receptor agonist in low oxygen level resulted in an enhanced expression of MMP-2/-9 in a time- and dose-dependent manner. In summary, this study indicates that trophoblastic adenosine A3 receptors are 1) modulated by oxygen tension, and 2) regulate MMP-2/-9 expression.
Similar content being viewed by others
References
Roberts JM, Taylor RN, Goldfien A. Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. Am J Hypertens. 1991;4:700–708.
Khong TY, Robertson WB. Spiral artery disease. In: Coulam CB, Faulk WP, McIntyre JA, eds. Immunological Obstetrics. New York: W.W. Norton & Company; 1992: 492–501.
Fisher SJ, Leitch MS, Kantor MS, Basbaum CB, Kramer RH. Degradation of extracellular matrix by the trophoblastic cells of first-trimester human placentas. J Cell Biochem. 1985;27:31–41.
Bode W, Maskos K. Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. Biol Chem. 2003;384:863–872.
Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta. 2000;1477:267–283.
Pilcher BK, Wang M, Qin XJ, Parks WC, Senior RM, Welgus HG. Role of matrix metalloproteinases and their inhibition in cutaneous wound healing and allergic contact hypersensitivity. Ann NY Acad Sci. 1999;878:12–24.
Chin JR, Werb Z. Matrix metalloproteinases regulate morphogenesis, migration and remodeling of epithelium, tongue skeletal muscle and cartilage in the mandibular arch. Development. 1997;124:1519–1530.
Heikinheimo K, Salo T. Expression of basement membrane type IV collagen and type IV collagenases (MMP-2 and MMP-9) in human fetal teeth. J Dent Res. 1995;74: 1226–1234.
Steffensen B, Hakkinen L, Larjava H. Proteolytic events of wound-healing—coordinated interactions among matrix metalloproteinases (MMPs), integrins, and extracellular matrix molecules. Crit Rev Oral Biol Med. 2001;12:373–398.
Konttinen YT, Ainola M, Valleala H, et al. Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis. Ann Rheum Dis. 1999;58:691–697.
Tetlow LC, Adlam DJ, Woolley DE. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum. 2001;44:585–594.
Huisman MA, Timmer A, Zeinstra M, et al. Matrixmetalloproteinase activity in first trimester placental bed biopsies in further complicated and uncomplicated pregnancies. Placenta. 2004;25:253–258.
Fernandez PL, Merino MJ, Nogales FF, Charonis AS, Stetler-Stevenson W, Liotta L. Immunohistochemical profile of basement membrane proteins and 72 kilo dalton type IV collagenase in the implantation placental site. An integrated view. Lab Invest. 1992;66:572–579.
Huppertz B, Kertschanska S, Demir AY, Frank HG, Kaufmann P. Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) during trophoblast invasion in the human placenta. Cell Tissue Res. 1998;291:133–148.
Shimonovitz S, Hurwitz A, Dushnik M, Anteby E, Geva-Eldar T, Yagel S. Developmental regulation of the expression of 72 and 92 kD type IV collagenases in human trophoblasts: a possible mechanism for control of trophoblast invasion. Am J Obstet Gynecol. 1994;171:832–838.
Merchant SJ, Crocker IP, Baker PN, Tansinda D, Davidge ST, Guilbert LJ. Matrix metalloproteinase release from placental explants of pregnancies complicated by intrauterine growth restriction. J Soc Gynecol Invest. 2004;11:97–103.
Shearer TW, Crosson CE. Adenosine A1 receptor modulation of MMP-2 secretion by trabecular meshwork cells. Invest Ophthalmol Vis Sci. 2002;43:3016–3020.
Ernens I, Rouy D, Velot E, Devaux Y, Wagner DR. Adenosine inhibits matrix metalloproteinase-9 secretion by neutrophils: implication of A2a receptor and cAMP/PKA/Ca2+ pathway. Circ Res. 2006;99:590–597.
Kim YH, Cho NH, Hwang HS, Kwon JY, Kang MH, Park YW. Differential expression of adenosine receptors in normal and preeclamptic human placentas. Kor J Obstet Gynecol. 2007;50:726–734.
Miller RK, Genbacev O, Turner MA, Aplin JD, Caniggia I, Huppertz B. Human placental explants in culture: approaches and assessments. Placenta. 2005;26:439–448.
Benyo DF, Miles TM, Conrad KP. Hypoxia stimulates cytokine production by villous explants from the human placenta. J Clin Endocrinol Metab. 1997;82:1582–1588.
American College of Obstetricians and Gynecologists Committee on Obstetric Practice. Diagnosis and management of preeclampsia and eclampsia. Int J Gynecol Obstet. 2002;77: 67–75 [ACOG practice bulletin].
Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of preeclampsia. Am J Reprod Immunol. 1997;37:240–249.
Dano K, Behrendt N, Hoyer-Hansen G, et al. Plasminogen activation and cancer. Thromb Haemost. 2005;93:676–681.
Bjorklund M, Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta. 2005;1755:37–69.
Van Belle H, Goossens F, Wynants J. Formation and release of purine catabolites during hypoperfusion, anoxia, and ischemia. Am J Physiol. 1987;252:H886–H893.
Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev. 1998;50:413–492.
Blay J, White TD, Hoskin DW. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 1997;57:2602–2605.
Gessi S, Cattabriga E, Avitabile A, et al. Elevated expression of A3 adenosine receptors in human colorectal cancer is reflected in peripheral blood cells. Clin Cancer Res. 2004;10:5895–5901.
Madi L, Ochaion A, Rath-Wolfson L, et al. The A3 adenosine receptor is highly expressed in tumor versus normal cells: potential target for tumor growth inhibition. Clin Cancer Res. 2004;10:4472–4479.
Rajakumar A, Whitelock KA, Weissfeld LA, Daftary AR, Markovic N, Conrad KP. Selective overexpression of the hypoxia-inducible transcription factor, HIF-2alpha, in placentas from women with preeclampsia. Biol Reprod. 2001;64:499–506.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–732.
Chen H-L, Yang Y, Hu X-L, Yelavarthi KK, Fishback JL, Hunt JS. Tumor necrosis factor alpha mRNA and protein are present in human placental and uterine cells at early and late stages of gestation. Am J Pathol. 1991;139:327–335.
Hu X-L, Yang Y, Hunt JS. Differential distribution of interleukin-1α and interleukin-1β proteins in human placentas. J Reprod Immunol. 1992;22:257–268.
Kameda T, Matsuzaki N, Sawai K, et al. Production of interleukin-6 by normal human trophoblast. Placenta. 1990;11:205–213.
Baker PN, Krasnow J, Roberts JM, Yeo KT. Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol. 1995;86:815–821.
Majka S, McGuire PG, Das A. Regulation of matrix metalloproteinase expression by tumor necrosis factor in a murine model of retinal neovascularization. Invest Ophthalmol Vis Sci. 2002;43:260–266.
Eichler W, Friedrichs U, Thies A, Tratz C, Wiedemann P. Modulation of matrix metalloproteinase and TIMP-1 expression by cytokines in human RPE cells. Invest Ophthalmol Vis Sci. 2002;43:2767–2773.
Montesinos MC, Shaw JP, Yee H, Shamamian P, Cronstein BN. Adenosine A2a receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis. Am J Pathol. 2004;164: 1887–1892.
Feoktistov I, Ryzhov S, Zhong H, et al. Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells toward an A2B angiogenic phenotype. Hypertension. 2004;44:649–654.
Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I. Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors. Circ Res. 2003;92: 485–492.
Merighi S, Benini A, Mirandola P, et al. Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells. Biochem Pharmacol. 2006;72:19–31.
Lockwood CJ, Oner C, Uz YH, et al. Matrix metalloproteinase 9 (MMP9) expression in preeclamptic decidua and MMP9 induction by tumor necrosis factor alpha and interleukin 1 beta in human first trimester decidual cells. Bio Reprod. 2008;78:1064–1072.
Almholt K, Johnsen M. Stromal cell involvement in cancer. Recent Results Cancer Res. 2003;162:31–43.
Pedersen TX, Pennington CJ, Almholt K, et al. Extracellular protease mRNAs are predominantly expressed in the stromal areas of microdissected mouse breast carcinomas. Carcinogenesis. 2005;26:1233–1240.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kim, YH., Hwang, HS., Kim, YT. et al. Modulation of Matrix Metalloproteinase Secretion by Adenosine A3 Receptor in Preeclamptic Villous Explants. Reprod. Sci. 15, 939–949 (2008). https://doi.org/10.1177/1933719108322431
Published:
Issue Date:
DOI: https://doi.org/10.1177/1933719108322431