Effect of impaired glucose tolerance during pregnancy on the expression of VEGF receptors in human placenta
M. Marini A , D. Vichi A , A. Toscano A , G. D. Zappoli Thyrion B , L. Bonaccini A , E. Parretti C , G. Gheri A , A. Pacini A and E. Sgambati A DA Department of Anatomy Histology and Forensic Medicine, University of Florence, Policlinic of Careggi, Viale Morgagni, 85, 50134, Florence, Italy.
B Department of Medicine, University of Florence, Policlinic of Careggi, Viale Pieraccini, 18, 50134, Florence, Italy.
C Department of Gynecology, Perinatology and Human Reproduction, University of Florence, Policlinic of Careggi, Viale Morgagni, 85, 50134, Florence, Italy.
D Corresponding author. Email: sgambati@unifi.it
Reproduction, Fertility and Development 20(7) 789-801 https://doi.org/10.1071/RD08032
Submitted: 19 February 2008 Accepted: 2 June 2008 Published: 1 August 2008
Abstract
The aim of the present study was to determine the expression of vascular endothelial growth factor (VEGF) receptors VEGFR-1, VEGFR-2 and VEGFR-3 in placentas from pregnancies complicated by altered glycaemia. Placentas from women with physiological pregnancies (Group 1), pregnancies complicated by minor degree of glucose intolerance (MDGI, Group 2) and by gestational diabetes mellitus (GDM) treated with insulin (Group 3) were collected. Immunohistochemistry, RT–PCR and western blot were employed to evaluate receptor expression. In the three study groups, VEGFR-1 immunoreactivity was detected in all the placental components. VEGFR-2 immunoreactivity was observed in the vessels of all the placentas from Groups 1 and 2, but only in some placentas of Group 3. VEGFR-3 reactivity was observed in all the components of Group 1; in Groups 2 and 3 reactivity was observed in some portions of the trophoblast or the whole trophoblast, and in the stroma. VEGFR-1 and VEGFR-2 mRNA levels in Groups 2 and 3 were significantly higher compared with Group 1, whereas those of VEGFR-3 were significantly lower. Receptor protein levels were significantly lower in Groups 2 and 3 compared with Group 1. These findings demonstrated dysregulation of expression of the three placental receptors, both in GDM and in MDGI.
Babawale, M. O. , Lovat, S. , Mayhew, T. M. , Lammiman, M. J. , James, D. K. , and Leach, L. (2000). Effects of gestational diabetes on junctional adhesion molecules in human term placental vasculature. Diabetologia 43, 1185–1196.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Bajoria, R. , Sooranna, S. R. , Ward, B. S. , and Chatterjee, R. (2002). Prospective function of placental leptin at maternal–fetal interface. Placenta 23, 103–115.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Berkus, M. D. , and Langer, O. (1993). Glucose tolerance test: degree of glucose abnormality correlates with neonatal outcome. Obstet. Gynecol. 81, 344–348.
| PubMed |
Biri, A. , Onan, A. , Devrim, E. , Babacan, F. , Kavutcu, M. , and Durak, I. (2006). Oxidant status in maternal and cord plasma and placental tissue in gestational diabetes. Placenta 27, 327–332.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248–254.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Carpenter, M. W. , and Coustan, D. R. (1982). Criteria for screening test for gestational diabetes. Am. J. Obstet. Gynecol. 144, 768–773.
| PubMed |
Cetin, I. , Santis, M. S. , and Taricco, E. (2005). Maternal and fetal amino acid concentrations in normal pregnancies and in pregnancies with gestational diabetes mellitus. Am. J. Obstet. Gynecol. 192, 610–617.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Challier, J. , Galtier, M. , Bintein, T. , Cortez, A. , Lepercq, J. , and Hauguel-de Mouzon, S. (2003). Placental leptin receptor isoforms in normal and pathological pregnancies. Placenta 24, 92–99.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Chen, J. , Tan, B. , Karteris, E. , Zervou, S. , Digby, J. , Hillhouse, E. W. , Vatish, M. , and Randeva, H. S. (2006). Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines. Diabetologia 49, 1292–1302.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Cheung, C. Y. (1997). Vascular endothelial growth factor: possible role in fetal development and placental function. J. Soc. Gynecol. Investig. 4, 169–177.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Clark, D. E. , Smith, S. K. , Sharkey, A. M. , and Charnock-Jones, D. S. (1996). Localization of VEGF and expression of its receptors flt and KDR in human placenta throughout pregnancy. Hum. Reprod. 11, 1090–1098.
| PubMed |
Cooper, J. C. , Sharkey, A. M. , McLaren, J. , Charnock-Jones, D. S. , and Smith, S. K. (1995). Localization of vascular endothelial growth factor and its receptor, flt, in human placenta and decidua by immunohistochemistry. J. Reprod. Fertil. 105, 205–213.
| PubMed |
Cooper, M. E. , Vranes, D. , Youssef, S. , Stacker, S. A. , and Cox, A. J. , et al. (1999). Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 48, 2229–2239.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Coughlan, M. T. , Vervaart, P. P. , Permezel, M. , Georgiou, H. M. , and Rice, G. E. (2004). Altered placental oxidative stress status in gestational diabetes mellitus. Placenta 25, 78–84.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Crocker, I. P. , Strachan, B. K. , Lash, G. E. , Cooper, S. , Warren, A. Y. , and Baker, P. N. (2001). Vascular endothelial growth factor but not placental growth factor promotes trophoblast syncytialisation in vitro. J. Soc. Gynecol. Investig. 8, 341–346.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
De Vries, C. , Escobedo, J. , Ueno, H. , Houch, K. , Ferrara, N. , and Williams, L. T. (1992). The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255, 989–991.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Demir, R. , Kayisli, U. A. , Seval, Y. , Celik-Ozenci, C. , Korgun, E. T. , Demir-Wensten, A. Y. , and Huppertz, B. (2004). Sequential expression of VEGF and its receptors in human placental villi during very early pregnancy: differences between placental vasculogenesis and angiogenesis. Placenta 25, 560–572.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Desoye, G. , Korgun, E. T. , Ghaffari-Tabrizi, N. , and Hahn, T. (2002). Is fetal macrosomia in adequately-controlled diabetic women the results of a placental defect? – a hypothesis. J. Matern. Fetal Neonatal Med. 11, 258–261.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Dunk, C. , and Ahmed, A. (2001). Expression of VEGF-C and activation of its receptors VEGFR-2 and VEGFR-3 in trophoblast. Histol. Histopathol. 16, 359–375.
| PubMed |
Enholm, B. , Jussila, L. , Karkkainen, M. , and Alitalo, K. (1998). Vascular endothelial growth factor-C: a growth factor for lymphatic and blood vascular endothelial cells. Trends Cardiovasc. Med. 8, 292–297.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Favier, J. , and Corvol, P. (2001). Physiological angiogenesis. Therapie 56, 455–463.
| PubMed |
Gaither, K. , Quraishi, A. N. , and Illsely, N. P. (1999). Diabetes alters the expression and activity of the human placental GLUT1 glucose transporter. J. Clin. Endocrinol. Metab. 84, 695–701.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Garcia Carrapato, M. R. (2003). The offspring of gestational diabetes. J. Perinat. Med. 31, 5–11.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Gu, B. , Alexander, J. S. , Gu, Y. , Zhang, Y. , Lewis, D. F. , and Wang, Y. (2006). Expression of lymphatic vascular endothelial hyaluronan receptor-1 (LYVE-1) in the human placenta. Lymphat. Res. Biol. 4, 11–17.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Hasan, R. N. , Phukan, S. , and Harada, S. (2003). Differential regulation of early growth response gene-1 expression by insulin and glucose in vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 23, 988–993.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Heinig, J. , Wilhem, S. , Muller, H. , Breise, V. , Bittorf, T. , and Brock, J. (2000). Determination of cytokine mRNA-expression in term human placenta of patients with gestational hypertension, intrauterine growth retardation and gestational diabetes mellitus using polymerase chain reaction. Zentralbl. Gynakol. 122, 413–418.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Helske, S. , Vourela, P. , Carpén, O. , Horning, C. , Weich, H. , and Halmesmäki, E. (2001). Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentae from normal and complicated pregnancies. Mol. Hum. Reprod. 7, 205–210.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Janota, J. , Pomyje, J. , Toth, D. , Sosna, O. , Živný, J. , Kuzel, D. , Straňák, Z. , Nečas, E. , and Živný, J. H. (2003). Expression of angiopoietic factors in normal and type-I diabetes human placenta: a pilot study. Eur. J. Obstet. Gynecol. Reprod. Biol. 111, 153–156.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Jansson, T. , Ekstrand, J. , Wennergren, M. , and Powell, T. L. (2001). Placental glucose transport in gestational diabetes mellitus. Am. J. Obstet. Gynecol. 184, 111–116.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Jansson, T. , Ekstrand, Y. , Björn, C. , Wennergren, M. , and Powell, T. L. (2002). Alteration in the activity of placental amino acid transporters in pregnancies complicated by diabetes. Diabetes 51, 2214–2219.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Jirkovská, M. , Kubinová, L. , Janácek, J. , Moravcová, M. , Krejcí, V. , and Karen, P. (2002). Topological properties and spatial organization of villous capillaries in normal and diabetic placentas. J. Vasc. Res. 39, 268–278.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Joukov, V. , Pajusola, K. , Kaipainen, A. , Chilov, D. , Lahtinen, I. , Kukk, E. , Saksala, O. , Kalkkinen, N. , and Alitalo, K. (1996). A novel vascular endothelial growth factor, VEGF-C, is the ligand for the Flt-4 receptor tyrosine kinase (VEGFR-3). EMBO J. 15, 290–298.
| PubMed |
Kaufmann, R. C. , McBride, P. , Amankwah, K. S. , and Huffman, D. G. (1992). The effect of minor degrees of glucose intolerance on the incidence of neonatal macrosomia. Obstet. Gynecol. 80, 97–101.
| PubMed |
Kim, B. S. , Chen, J. , Weinstein, T. , Noiri, E. , and Goligorsky, M. S. (2002). VEGF expression in hypoxia and hyperglycaemia: reciprocal effect on branching angiogenesis in epithelial–endothelial co-cultures. J. Am. Soc. Nephrol. 13, 2027–2036.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
King, R. G. , Osmond, D. T. , Brennecke, S. P. , and Gude, N. M. (2003). Effect of fetal macrosomia on human placental glucose transport and utilization in insulin-treated gestational diabetes. J. Perinat. Med. 31, 475–483.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Kingdom, J. , Huppertz, B. , Seaward, G. , and Kaufmann, P. (2000). Development of the placental villous tree and its consequences for fetal growth. Eur. J. Obstet. Gynecol. Reprod. Biol. 92, 35–43.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Klagsbrun, M. , and D’Amore, P. (1996). Vascular endothelial growth factor and its receptors. Cytokine Growth Factor Rev. 7, 259–270.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Lash, G. E. , Cartwright, J. E. , Whitley, G. S. , Trew, A. J. , and Baker, P. N. (1999). The effects of angiogenic growth factors on extravillous trophoblast invasion and motility. Placenta 20, 661–667.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Lea, R. G. , Howe, D. , Hannah, L. T. , Bonneau, O. , Hunter, L. , and Hoggard, N. (2000). Placental leptin in normal, diabetic and fetal growth-retarded pregnancies. Mol. Hum. Reprod. 6, 763–739.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Madazli, R. , Tuten, A. , Calay, Z. , Uzun, H. , Uludag, S. , and Ocak, V. (2008). The incidence of placental abnormalities, maternal and cord plasma malondialdehyde and vascular endothelial growth factor levels in women with gestational diabetes mellitus and nondiabetic control. Gynecol. Obstet. Invest. 65, 227–232.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Maglione, D. , Guerriero, V. , Viglietto, G. , Delli-Bovi, P. , and Persico, M. G. (1991). Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc. Natl. Acad. Sci. USA 88, 9267–9271.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Mayhew, T. M. , and Sampson, C. (2003). Maternal diabetes mellitus is associated with altered deposition of fibrin-type fibrinoid at the villous surface in term placentae. Placenta 24, 524–531.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Moses, R. G. , and Calvert, D. (1995). Pregnancy outcomes in women without gestational diabetes mellitus to the maternal glucose level. Is there a continuum of risk? Diabetes Care 18, 1527–1533.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Myatt, L. , and Cui, X. (2004). Oxidative stress in the placenta. Histochem. Cell Biol. 122, 369–382.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Ni, Y. , May, V. , Braas, K. , and Osol, G. (1997). Pregnancy augments uteroplacental vascular endothelial growth factor gene expression and vasodilator effects. Am. J. Physiol. 273, H938–H944.
| PubMed |
Osmond, D. T. D. , King, R. G. , Brennecke, S. P. , and Gude, N. M. (2001). Placental glucose transport and utilisation is altered at term in insulin-treated, gestational-diabetic patients. Diabetologia 44, 1133–1139.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Page, N. M. , Kemp, C. F. , Butlin, D. J. , and Lowry, P. J. (2002). Placental peptides as markers of gestational disease. Reproduction 123, 487–495.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Parretti, E. , Carignani, L. , Cioni, R. , Bartoli, E. , Borri, P. , La Torre, P. , Mecacci, F. , Martini, E. , Scarselli, G. , and Mello, G. (2003). Sonographic evaluation of fetal growth and body composition in women with different degrees of normal glucose metabolism. Diabetes Care 26, 2741–2748.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Persson, A. , Johansson, M. , Jansson, T. , and Powell, T. L. (2002). Na+/K+-ATPase activity and expression in syncytiotrophoblast plasma membrane in pregnancies complicated by diabetes. Placenta 23, 386–391.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Pietryga, M. , Biczysko, W. , Wender-Ozegowska, E. , Brazert, J. , Bieganska, E. , and Biczysko, R. (2004). Ultrastructure examination of the placenta in pregnancy complicated by diabetes mellitus. Ginekol. Pol. 75, 111–118.
| PubMed |
Radaelli, T. , Varastehpour, A. , Catalano, P. , and Hauguel-de Monzon, S. (2003). Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes 52, 2951–2958.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Saldeen, P. , Olofsson, P. , and Laurini, R. N. (2002a). Signs of platelet activation, but not lipid peroxidation, in fetal blood associated with functional and structural umbilicoplacental lesions in pregnancies complicated by impaired glucose metabolism. J. Matern. Fetal Neonatal Med. 12, 165–171.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Saldeen, P. , Olofsson, P. , and Laurini, R. N. (2002b). Structural, functional and circulatory placental changes associated with impaired glucose metabolism. Eur. J. Obstet. Gynecol. Reprod. Biol. 105, 136–142.
| PubMed |
Sgambati, E. , Marini, M. , Zappoli Thyrion, G. D. , Parretti, E. , Mello, G. , Orlando, C. , Simi, L. , Tricarico, C. , Gheri, G. , and Brizzi, E. (2004). VEGF expression in the placenta from pregnancies complicated by hypertensive disorders. BJOG 111, 564–570.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Sgambati, E. , Marini, M. , Vichi, D. , Zappoli Thyrion, G. D. , Parretti, E. , Mello, G. , and Gheri, G. (2007). Distribution of the glycoconjugate oligosaccharides in the human placenta from pregnancies complicated by altered glycaemia: lectin histochemistry. Histochem. Cell Biol. 128, 263–273.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Shore, V. H. , Wang, T. H. , Wang, C. L. , Torry, R. J. , Caudle, M. R. , and Torry, D. S. (1997). Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast. Placenta 18, 657–665.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Szukiewicz, D. , Szukiewicz, A. , Maslinska, D. , Szewczyk, G. , and Watroba, M. (2003). Mast cell-derived vascular endothelial growth factor (VEGF) and microvascular density in diabetic placentae. Inflamm. Res. 52((Suppl. 1)), S9–S10.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Taylor, C. M. , Stevens, H. , Anthony, F. W. , and Wheeler, T. (1997). Influence of hypoxia on vascular endothelial growth factor and chorionic gonadotrophin production in the trophoblast-derived cell lines: JEG, Jar and BeWo. Placenta 18, 451–458.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Terman, B. I. , Dougher-Vermazen, M. , Carrion, M. E. , Dimitrov, D. , Armellino, D. C. , Gospodarowicz, D. , and Böhlen, P. (1992). Identification of the KDR tyrosine kinase as a receptor for vascular endothelial growth factor. Biochem. Biophys. Res. Commun. 187, 1579–1586.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Thomas, A. , Kaur, S. , and Somville, T. (2002). Abnormal glucose screening test followed by normal glucose tolerance test and pregnancy outcome. Saudi Med. J. 23, 814–818.
| PubMed |
Torry, D. S. , and Torry, R. J. (1997). Angiogenesis and the expression of vascular endothelial growth factor in endometrium and placenta. Am. J. Reprod. Immunol. 37, 21–29.
| PubMed |
Vuorela, P. , and Halmesmäki, E. (2006). Vascular endothelial growth factor, its receptors, and the Tie receptors in the placental bed of women with preeclampsia, diabetes, and intrauterine growth retardation. Am. J. Perinatol. 23, 255–264.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Vuorela, P. , Hatva, E. , Lymbaussakis, A. , Kaipainen, A. , Joukov, V. , Persico, M. G. , Alitalo, K. , and Halmesmaki, E. (1997). Expression of vascular endothelial growth factor and placenta growth factor in human placenta. Biol. Reprod. 56, 489–494.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Yang, W. C. , Su, T. H. , Yang, Y. C. , Chang, S. C. , Chen, C. Y. , and Chen, C. P. (2005). Altered perlecan expression in placental development and gestational diabetes mellitus. Placenta 26, 780–788.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Younes, B. , Baez-Giangreco, A. , al-Nuaim, L. , al-Hakeem, A. , and Abu Talib, Z. (1996). Basement membrane thickening in the placenta from diabetic women. Pathol. Int. 46, 100–104.
| PubMed |
Zhao, B. , Cai, J. , and Boulton, M. (2004). Expression of placenta growth factor is regulated by both VEGF and hyperglycaemia via VEGFR-2. Microvasc. Res. 68, 239–246.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zygmunt, M. (2001). Placental circulation: Clinical significance. Early Pregnancy 5, 72–73.
| PubMed |