Transient Local Overexpression of Human Vascular Endothelial Growth Factor (VEGF) in Mouse Feto-maternal Interface during Mid-term Pregnancy Lowers Systemic Maternal Blood Pressure

Abstract

The effect on maternal circulation of transient human vascular endothelial growth factor (VEGF)₁₆₅ cDNA transfection into the mouse feto-maternal interface at day 14.5 post coitus (p.c.) using a hemagglutinating virus of Japan-envelope (HVJ-E) vector system is reported. On day 15.5 p.c., Western blotting clearly showed overexpression of 18 kD VEGF protein in the uterus. After VEGF transfection, the blood pressure was significantly lowered for 48 hours. On day 17.5 p.c., the blood pressure returned to the control level. Proteinuria was not observed after VEGF transfection. No preterm birth was observed during the course of pregnancy after the transfection procedure. After 24 hours of transfection, human VEGF was not detectable and the mouse VEGF level was similar to that in peripheral blood. However, the soluble fms-like tyrosine kinase (Flt)-1 concentration was significantly lower in VEGF-transfected mice. These results suggest that extraamniotic VEGF overexpression lowered the systemic blood pressure without altering the VEGF concentration in the peripheral blood. Local overexpression of VEGF may become a novel treatment for pregnancy-related disorders such as hypertension complicated-pregnancy and preeclampsia.

Key words

HVJ-E (hemagglutinating virus of Japan-envelope) vector - preeclampsia - extraamniotic space - in vivo gene transfer

References

• 1 Cunningham FG, Gant NF, Leveno KJ, Gilstrap III LC, Hauth JC, Wenstrom KD. Williams Obstetrics 21st ed. McGraw-Hill, New York 2001: 181-185
• 2 Shweiki D, Itin A, Neufeld G, Gitay-Goren H, Keshet E. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggests a role in hormonally-regulated angiogenesis.  J Clin Invest. 1993;  91 2235-2243
• 3 Sharkey AM, Charnock-Jones DS, Boocock CA, Brown KD, Smith SK. Expression of mRNA for vascular endothelial growth factor in human placenta.  J Reprod Fertil. 1993;  99 609-615
• 4 Shiraishi S, Nakagawa K, Kinukawa N, Nakano H, Sueishi K. Immunohistochemical localization of vascular endothelial growth factor in the human placenta.  Placenta. 1996;  13 111-121
• 5 Ni Y, May V, Braas K, Osol G. Pregnancy augments uteroplacental vascular endothelial growth factor gene expression and vasodilator effects.  Am J Physiol. 1997;  273 H938-H944
• 6 Kaufmann P, Mayhew TM, Charnock-Jones DS. Aspects of human fetoplacental vasculogenesis and angiogenesis. II, Changes during normal pregnancy.  Placenta. 2004;  25 114-126
• 7 Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the risk of preeclampsia.  N Engl J Med. 2004;  350 672-683
• 8 Aliello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins.  Proc Natl Acad Sci USA. 1995;  92 10457-10461
• 9 Sibai B, Dekker G, Kupferminic M. Preeclampsia.  Lancet. 2005;  365 785-799
• 10 Nakamura H, Kimura T, Ikegami H, Ogita K, Koyama S, Shimoya K, Tsujie T, Koyama M, Kaneda Y, Murata Y. Highly efficient and minimally invasive in vivo gene transfer to the mouse uterus using haemagglutinating virus of Japan (HVJ) envelope vector.  Mol Hum Reprod. 2003;  9 603-609
• 11 Koyama S, Kimura T, Ogita K, Nakamura H, Tabata C, Khan MAHNA, Kumiko Temma-Asano K, Shimoya K, Tsutsui T, Koyama M, Kaneda Y, Murata Y. Simple and highly efficient method for transient in vivo gene transfer to mid-late pregnant mouse uterus.  J Reprod Immunol. 2006;  , Feb 16 [Epub ahead of print]
• 12 Sambrook J, Russell DW. Molecular Cloning, A laboratory manual, 3rd ed. Cold Spring Harbor, New York 2001: A8.40-A8.55
• 13 Sutoo D, Akiyama K, Takita H. Hypertension in epileptic mice: a phenomenon related to reduction of Ca²⁺-dependent catecholamine synthesis in the brain.  Eur J Pharmacol. 1995;  278 33-37
• 14 Daftary GS, Taylor HS. Reproductive tract gene transfer.  Fertil Steril. 2003;  80 475-484
• 15 Kakizawa H, Itoh Y, Imamura S, Matsumoto T, Ishiwata Y, Ono Y, Yamamoto K, Kato T, Hayakawa N, Oda N, Goto Y, Goto Y, Nagasaka A, Senda T, Itoh M. Possible role of VEGF in the progression of kidney disease in streptozotocin (STZ)-induced diabetic rats: effect of an ACE inhibitor and angiotensin II receptor antagonist.  Horm Metab Res. 2004;  36 458-464
• 16 Schrijvers BF, De Vriese AS, Tilton RG, Van de Voorde J, Denner L, Lameire NH, Flyvbjerg A. Inhibition of vascular endothelial growth factor (VEGF) does not affect early renal changes in a rat model of lean type 2 diabetes.  Horm Metab Res. 2005;  37 21-25
• 17 He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB. Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src.  J Biol Chem. 1999;  274 25130-25135
• 18 Kumazaki K, Nakayama M, Suehara N, Wada Y. Expression of vascular endothelial growth factor, placental growth factor, and their receptors Flt-1 and KDR in human placenta under pathologic conditions.  Hum Pathol. 2002;  33 1069-1077
• 19 Sugino N, Kashida S, Karube-Harada A, Takiguchi S, Kato H. Expression of vascular endothelial growth factor (VEGF) and its receptors in human endometrium throughout the menstrual cycle and in early pregnancy.  Reproduction. 2002;  123 379-387
• 20 He Y, Smith SK, Day KA, Clark DE, Licence DR, Charnock-Jones DS. 1999 Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for regulation of VEGF activity.  Mol Endocrinol. 1999;  13 537-545
• 21 Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response through primigravid pregnancy.  J Clin Invest. 1973;  52 2682-2689
• 22 Maynard SE, Min J-Y, Merchan J, Lim K-H, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. 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
• 23 Takimoto-Ohnishi E, Saito T, Ishida J, Ohnishi J, Sugiyama F, Yagami K, Fukamizu A. Differential roles of rennin and angiotensinogen in the feto-maternal interface in the development of complications of pregnancy.  Mol Endocrinol. 2005;  19 1361-1372
• 24 Kanayama N, Takahashi K, Matsuura T, Sugimura M, Kobayashi T, Moniwa N, Tomita M, Nakayama K. Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice.  Mol Hum Reprod. 2002;  8 1129-1135
• 25 Salamalekis E, Kassanos D, Hassiakos D, Chrelias C, Ghristodoulakos G. Intra/extra-amniotic administration of prostaglandin F2α in fetal death, missed and therapeutic abortions.  Clin Exp Obstet Gynecol. 1990;  17 17-21

Correspondence