Exogenous Vascular Endothelial Growth Factor Can Induce Preeclampsia-Like Symptoms in Pregnant Mice

Yusuke Murakami; Takao Kobayashi; Kohei Omatsu; Mika Suzuki; Ryota Ohashi; Toshiki Matsuura; Motoi Sugimura; Naohiro Kanayama

doi:10.1055/s-2005-872437

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2005; 31(3): 307-313
DOI: 10.1055/s-2005-872437

Exogenous Vascular Endothelial Growth Factor Can Induce Preeclampsia-Like Symptoms in Pregnant Mice

Yusuke Murakami¹ , Takao Kobayashi² , Kohei Omatsu¹ , Mika Suzuki¹ , Ryota Ohashi¹ , Toshiki Matsuura¹ , Motoi Sugimura¹ , Naohiro Kanayama¹

¹Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Hamamatsu, Japan
²Professor, Department of Family and Child Nursing, and Midwifery, Shinshu University School of Health Sciences, Matsumoto, Japan

Abstract

ABSTRACT

It is reported that expression of vascular endothelial growth factor (VEGF) in trophoblasts increases in cases with preeclampsia. Recently, we demonstrated that the lack of cyclin-dependent kinase inhibitor, p57kip2, expression in the fetus and the placenta plays a role in the development of preeclampsia-like symptoms in pregnant mice. Furthermore, we observed that VEGF mRNA and protein levels, especially VEGF₁₆₄, were higher and its expression was stronger in placentas of p57kip2-null embryos than in placentas of wild-type embryos. In this study we investigated whether exogenous murine VEGF₁₆₄ induced preeclampsia-like symptoms in pregnant mice, and anti-VEGF neutralized antibody could suppress these symptoms. Administration of VEGF induced hypercoagulation in the placental circulation and a significant elevation of systolic blood pressure in pregnant mice. Furthermore, we demonstrated that treatment with anti-VEGF antibody could suppress the hypercoagulability in placenta and the elevation of systolic blood pressure. These data suggest that VEGF is related to the pathophysiology of preeclampsia.

KEYWORDS

Vascular endothelial growth factor (VEGF) - hypertension - hypercoagulation - preeclampsia - anti-VEGF antibody

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Referenzen

REFERENCES

1 Lash G E, Cartwright J E, Whitley G S, Trew A J, Baker P N. The effects of angiogenic growth factors on extravillous trophoblast invasion and motility. Placenta. 1999; 20 661-667
2 Ghosh D, Sharkey A M, Charnock-Jones D S et al.. Expression of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in conceptus and endometrium during implantation in the rhesus monkey. Mol Hum Reprod. 2000; 6 935-941
3 Matsuura T, Takahashi K, Nakayama K et al.. Increased expression of vascular endothelial growth factor in placentas of p57(Kip2) null embryos. FEBS Lett. 2002; 532 283-288
4 Petersen T M, Larsen T, Nielsen H J. Angiogenic proteins: possible markers of physiopathological processes during fetal development. Ugeskr Laeger. 2003; 165 3082-3087
5 Achen M G, Gad J M, Stacker S A, Wilks A F. Placenta growth factor and vascular endothelial growth factor are co-expressed during early embryonic development. Growth Factors. 1997; 15 69-80
6 Tsatsaris V, Goffin F, Munaut C et al.. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab. 2003; 88 5555-5563
7 Winther H, Ahmed A, Dantzer V. Immunohistochemical localization of vascular endothelial growth factor (VEGF) and its two specific receptors, Flt-1 and KDR, in the porcine placenta and non-pregnant uterus. Placenta. 1999; 20 35-43
8 Cheung C Y. Vascular endothelial growth factor: possible role in fetal development and placental function. J Soc Gynecol Investig. 1997; 4 169-177
9 Reuvekamp A, Velsing-Aarts F V, Poulina I E, Capello J J, Duits A J. Selective deficit of angiogenic growth factors characterizes pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecol. 1999; 106 1019-1022
10 Hefler L, Obermair A, Husslein P, Kainz C, Tempfer C. Vascular endothelial growth factor serum levels in pregnancy and preeclampsia. Acta Obstet Gynecol Scand. 2000; 79 77-78
11 Hunter A, Aitkenhead M, Caldwell C, McCracken G, Wilson D, McClure N. Serum levels of vascular endothelial growth factor in preeclamptic and normotensive pregnancy. Hypertension. 2000; 36 965-969
12 Brockelsby J C, Anthony F W, Johnson I R, Baker P N. The effects of vascular endothelial growth factor on endothelial cells: a potential role in preeclampsia. Am J Obstet Gynecol. 2000; 182 176-183
13 Zhang P, Liegeois N J, Wong C et al.. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature. 1997; 387 151-158
14 Takahashi K, Nakayama K, Nakayama K. Mice lacking a CDK inhibitor, p57Kip2, exhibit skeletal abnormalities and growth retardation. J Biochem (Tokyo). 2000; 127 73-83
15 Yan Y, Frisen J, Lee M H, Massague J, Barbacid M. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev. 1997; 11 973-983
16 Kanayama N, Takahashi K, Matsuura T et al.. Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice. Mol Hum Reprod. 2002; 8 1129-1135
17 Shintani S, Li C, Ishikawa T, Mihara M, Nakashiro K, Hamakawa H. Expression of vascular endothelial growth factor A, B, C, and D in oral squamous cell carcinoma. Oral Oncol. 2004; 40 13-20
18 Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 2000; 60 203-212
19 Senger D R, Galli S J, Dvorak A M, Perruzzi C A, Harvey V S, Dvorak H F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983; 219 983-985
20 Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico M G. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A. 1991; 88 9267-9271
21 Olofsson B, Pajusola K, Kaipainen A et al.. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci U S A. 1996; 93 2576-2581
22 Joukov V, Kaipainen A, Jeltsch M et al.. Vascular endothelial growth factors VEGF-B and VEGF-C. J Cell Physiol. 1997; 173 211-215
23 Lee J, Gray A, Yuan J, Luoh S M, Avraham H, Wood W I. Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci U S A. 1996; 93 1988-1992
24 Achen M G, Jeltsch M, Kukk E et al.. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A. 1998; 95 548-553
25 Meyer M, Clauss M, Lepple-Wienhues A et al.. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signaling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J. 1999; 18 363-374
26 Tischer E, Mitchell R, Hartman T et al.. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991; 266 11947-11954
27 Houck K A, Ferrara N, Winer J, Cachianes G, Li B, Leung D W. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991; 5 1806-1814
28 Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997; 18 4-25
29 Vincenti V, Cassano C, Rocchi M, Persico G. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3 Circulation. 1996; 93 1493-1495
30 Leung D W, Cachianes G, Kuang W J, Goeddel D V, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989; 246 1306-1309
31 Keck P J, Hauser S D, Krivi G et al.. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989; 246 1309-1312
32 Bosio P M, Wheeler T, Anthony F, Conroy R, O'herlihy C, McKenna P. Maternal plasma vascular endothelial growth factor concentrations in normal and hypertensive pregnancies and their relationship to peripheral vascular resistance. Am J Obstet Gynecol. 2001; 184 146-152
33 Baker P N, Krasnow J, Roberts J M, Yeo K T. Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol. 1995; 86 815-821
34 Sharkey A M, Cooper J C, Balmforth J R et al.. Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre-eclampsia. Eur J Clin Invest. 1996; 26 1182-1185
35 Maynard S E, Min J Y, Merchan J et al.. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003; 111 649-658
36 Levine R J, Maynard S E, Qian C et al.. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004; 350 672-683

Takao KobayashiM.D. Ph.D. Professor

Department of Family and Child Nursing, and Midwifery, Shinshu University School of Health Sciences

3-1-1 Asahi, Matsumoto City

Nagano Prefecture 390-8621, Japan

eMail: tkoba@shinshu-u.ac.jp