Expression of vascular endothelial growth factor receptor types 1, 2 and 3 in placenta from pregnancies complicated by hypertensive disorders
M. Marini A , D. Vichi A , A. Toscano A , G. D. Zappoli Thyrion B , E. Parretti C , G. Mello C , G. Gheri A , A. Pacini A and E. Sgambati A D
+ Author Affiliations
- Author Affiliations
A 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 19(5) 641-651 https://doi.org/10.1071/RD06131
Submitted: 25 September 2006 Accepted: 23 April 2007 Published: 1 June 2007
Abstract
The aim of the present study was to determine the expression of vascular endothelial growth factor (VEGF) family receptors (VEGFR) in placentas from pregnancies complicated by hypertensive disorders of different clinical severity. Placental tissue from women with gestational hypertension, pre-eclampsia, pre-eclampsia with haemolysis, elevated liver enzymes and low platelets (HELLP syndrome) and normotensive women, as a control group, was examined. Immunohistochemical techniques, reverse transcription–polymerase chain reaction and western blot were used to evaluate receptor expression. In cases with gestational hypertension, as well as in control cases, VEGFR-1 and VEGFR-3 immunoreactivity was detected in all placental components, whereas in placentas from the pre-eclampsia and pre-eclampsia with HELLP syndrome groups, VEGFR-1 and VEGFR-3 immunoreactivity was detected only in some portions of trophoblast and/or some vessels and/or clusters of stromal cells. In the control group, VEGFR-2 immunoreactivity was observed only in the vessels, whereas the hypertensive groups showed VEGF-2 immunoreactivity also in trophoblast and stromal cells. The mRNA levels of the three receptors in the group with gestational hypertension were higher with respect to those in the control group. Placentas from pregnancies with pre-eclampsia showed lowest mRNA expression levels, whereas placentas from women with pre-eclampsia plus HELLP syndrome showed higher mRNA expression levels with respect to the three other groups. Receptor protein levels were lower in pathological cases compared with levles in the control group. These findings demonstrate a dysregulation of placental expression of VEGF family receptors related to the degree of clinical severity of the hypertensive disorder.
References
Ahmed, A. , Dunk, C. , Ahmad, S. , and Khaliq, A. (2000). Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PLGF) and soluble Flt-1 by oxygen: a review. Placenta (Suppl. A) 21, S16–S24.
| Crossref | GoogleScholarGoogle Scholar |
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 |
Brockelsby, J. C. , Anthony, F. W. , Johnson, I. R. , and Baker, P. N. (2000). The effects of vascular endothelial growth factor on endothelial cells: a potential role in preeclampsia. Am. J. Obstet. Gynecol. 182, 176–183.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Cheng, Z. , Lin, Q. , and Shen, Z. (2001). Study on association of vascular endothelial growth factor with the pathogenesis of pregnancy induced hypertension. Zhonghua Fu Chaan Ke Za Zhi 36, 72–75.[In Chinese]
Cheung, C. Y. (1997). Vascular endothelial growth factor: possible role in fetal development and placental function. J. Soc. Gynecol. Invest. 4, 169–177.
| Crossref | GoogleScholarGoogle Scholar |
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, J. C. , Sharkey, A. M. , Charnock-Jones, D. S. , Palmer, C. R. , and Smith, S. K. (1996). VEGF mRNA levels in placentae from pregnancies complicated by pre-eclampsia. Br. J. Obstet. Gynaecol. 103, 1191–1196.
| 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 syncytialization in vitro. J. Soc. Gynecol. Invest. 8, 341–346.
| Crossref | GoogleScholarGoogle Scholar |
Damsky, C. H. , and Fisher, S. J. (1998). Trophoblast pseudo-vasculogenesis: faking it with endothelial adhesion receptors. Curr. Opin. Cell Biol. 10, 660–666.
| 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 |
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 |
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 |
El-Salahy, E. M. , Ahmed, M. I. , El-Gharieb, A. , and Tawfik, H. (2001). New scope in angiogenesis: role of vascular endothelial growth factor (VEGF), NO, lipid peroxidation, and vitamin E in the pathophysiology of pre-eclampsia among Egyptian females. Clin. Biochem. 34, 323–329.
| Crossref | GoogleScholarGoogle Scholar | 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 |
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 |
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 |
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 |
Kaushal, V. , Mukunyadzi, P. , Dennis, R. A. , Siegel, E. R. , Jhonson, D. E. , and Kahli, M. (2005). Stage-specific characterization of the vascular endothelial growth factor axis in prostate cancer: expression of lymphangiogenic markers is associated with advanced-stage disease. Clin. Cancer Res. 11, 584–593.
| 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 Factors Rev. 7, 259–270.
| Crossref | GoogleScholarGoogle Scholar |
Kumazaki, K. , Nakayama, M. , Suehara, N. , and Yoshinao, W. (2002). Expression of vascular endothelial growth factor, placental growth factor, and their receptors flt-1 and KDR in human placenta under pathologic conditions. Hum. Pathol. 33, 1069–1077.
| 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 |
Lyall, F. , Yong, A. , Boswell, F. , Kingdom, J. C. P. , and Greer, I. A. (1997). Placental expression of vascular endothelial growth factor in placentae from pregnancies complicated by pre-eclampsia and intrauterine growth restriction does not support placental hypoxia. Placenta 18, 269–276.
| 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 |
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, 938–944.
Pijinenborg, R. (1994). Trophoblast invasion. Reprod. Med. Rev. 3, 53–73.
Ranheim, T. , Staff, A. C. , and Henriksen, T. (2001). VEGF mRNA is unaltered in decidual and placental tissues in preeclampsia at delivery. Acta Obstet. Gynecol. Scand. 80, 93–98.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Redman, C. W. , and Sargent, I. L. (2001). The pathogenesis of pre-eclampsia. Gynecol. Obstet. Fertil. 29, 518–522.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Roberts, J. M. , and Redman, C. W. G. (1993). Pre-eclampsia: more than pregnancy-induced hypertension. Lancet 341, 1447–1451.
| Crossref | GoogleScholarGoogle Scholar | 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. Br. J. Obstet. Gynaecol. 111, 564–570.
| Crossref | GoogleScholarGoogle Scholar |
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 |
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. , Dougher-Vermazen, M. , Carrion, M. E. , Dimitrov, D. , Armellino, D. C. , Gospodarowicz, D. , and Bohlen, 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 |
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 |
Tsatsaris, V. , Goffin, F. , Munaut, C. , Brichout, J. F. , Pignon, M. R. , Noel, A. , Scheaps, J. P. , Cabrol, D. , Frankenne, F. , and Foidart, J. M. (2003). Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J. Clin. Endocrinol. Metab. 88, 5555–5563.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Tsokos, M. , Longauer, F. , Kardosova, V. , Gavel, A. , Anders, S. , and Schulz, F. (2002). Maternal death in pregnancy from HELLP syndrome. A report of three medico-legal autopsy cases with special reference to distinctive histopathological alterations. Int. J. Legal Med. 116, 50–53.
| 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 |
Zhou, Y. , Damsky, C. H. , and Fisher, S. J. (1997). Preeclampsia is associated with failure of human cytotrophoblast to mimic a vascular adhesion phenotype: one cause of defective endovascular invasion in this syndrome? J. Clin. Invest. 99, 2152–2164.
| PubMed |
Zhou, Y. , McMaster, M. , Woo, K. , Janatpour, M. , Perry, J. , Kortonen, T. , Alitalo, K. , Damsky, C. , and Fisher, S. J. (2002). Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am. J. Pathol. 160, 1405–1423.
| PubMed |
