title: Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.
abstract: Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia.
authors.affiliation: From the Department of Surgery (F.T.S.), Department of Physiology and Biophysics (F.T.S., J.P.G.), and Cardiovascular-Renal Research Center (F.T.S., J.P.G.), The University of Mississippi Medical Center, Jackson; Aggamin Biologics, New York, NY (A.Y.T., W.S.J., G.D., P.K.); and Beth Israel Deaconess Medical Center, Department of Nephrology, Harvard Medical School, Boston, MA (S.A.K.). jgranger@umc.edu fspradley@umc.edu.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Spradley
authors.affiliation: From the Department of Surgery (F.T.S.), Department of Physiology and Biophysics (F.T.S., J.P.G.), and Cardiovascular-Renal Research Center (F.T.S., J.P.G.), The University of Mississippi Medical Center, Jackson; Aggamin Biologics, New York, NY (A.Y.T., W.S.J., G.D., P.K.); and Beth Israel Deaconess Medical Center, Department of Nephrology, Harvard Medical School, Boston, MA (S.A.K.).
authors.forename: Adelene Y
authors.initials: AY
authors.lastname: Tan
authors.affiliation: From the Department of Surgery (F.T.S.), Department of Physiology and Biophysics (F.T.S., J.P.G.), and Cardiovascular-Renal Research Center (F.T.S., J.P.G.), The University of Mississippi Medical Center, Jackson; Aggamin Biologics, New York, NY (A.Y.T., W.S.J., G.D., P.K.); and Beth Israel Deaconess Medical Center, Department of Nephrology, Harvard Medical School, Boston, MA (S.A.K.).
authors.forename: Woo S
authors.initials: WS
authors.lastname: Joo
authors.affiliation: From the Department of Surgery (F.T.S.), Department of Physiology and Biophysics (F.T.S., J.P.G.), and Cardiovascular-Renal Research Center (F.T.S., J.P.G.), The University of Mississippi Medical Center, Jackson; Aggamin Biologics, New York, NY (A.Y.T., W.S.J., G.D., P.K.); and Beth Israel Deaconess Medical Center, Department of Nephrology, Harvard Medical School, Boston, MA (S.A.K.).
authors.forename: Garrett
authors.initials: G
authors.lastname: Daniels
authors.affiliation: From the Department of Surgery (F.T.S.), Department of Physiology and Biophysics (F.T.S., J.P.G.), and Cardiovascular-Renal Research Center (F.T.S., J.P.G.), The University of Mississippi Medical Center, Jackson; Aggamin Biologics, New York, NY (A.Y.T., W.S.J., G.D., P.K.); and Beth Israel Deaconess Medical Center, Department of Nephrology, Harvard Medical School, Boston, MA (S.A.K.).
authors.forename: Paul
authors.initials: P
authors.lastname: Kussie
authors.affiliation: From the Department of Surgery (F.T.S.), Department of Physiology and Biophysics (F.T.S., J.P.G.), and Cardiovascular-Renal Research Center (F.T.S., J.P.G.), The University of Mississippi Medical Center, Jackson; Aggamin Biologics, New York, NY (A.Y.T., W.S.J., G.D., P.K.); and Beth Israel Deaconess Medical Center, Department of Nephrology, Harvard Medical School, Boston, MA (S.A.K.).
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.affiliation: From the Department of Surgery (F.T.S.), Department of Physiology and Biophysics (F.T.S., J.P.G.), and Cardiovascular-Renal Research Center (F.T.S., J.P.G.), The University of Mississippi Medical Center, Jackson; Aggamin Biologics, New York, NY (A.Y.T., W.S.J., G.D., P.K.); and Beth Israel Deaconess Medical Center, Department of Nephrology, Harvard Medical School, Boston, MA (S.A.K.). jgranger@umc.edu fspradley@umc.edu.
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D046110:Hypertension, Pregnancy-Induced / Q000188:drug therapy* / Q000209:etiology; D007511:Ischemia / Q000150:complications* / Q000188:drug therapy; D018384:Oxidative Stress / Q000502:physiology; D010920:Placenta / Q000098:blood supply* / Q000378:metabolism; D000072483:Placenta Growth Factor; D021041:Placental Circulation / Q000187:drug effects / Q000502:physiology; D010927:Placental Insufficiency; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000209:etiology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism / Q000494:pharmacology*; D011270:Pregnancy, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D018570:Risk Assessment
chemical_list: C000608036:PGF protein, human; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor
keywords: RUPP; blood pressure; preeclampsia; pregnancy; rat
references.citation: PLoS One. 2015;10(4):e0124684
references.pmid: 25906026
references.citation: Cold Spring Harb Perspect Med. 2012;2(8). pii: a011056. doi: 10.1101/cshperspect.a011056
references.pmid: 22908198
references.citation: Am J Hypertens. 2008 Oct;21(10):1152-6
references.pmid: 18670418
references.citation: Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2080-4
references.pmid: 17644567
references.citation: Angiogenesis. 2012 Jun;15(2):171-85
references.pmid: 22302382
references.citation: Hypertension. 2010 Feb;55(2):380-5
references.pmid: 20026764
references.citation: Eur J Obstet Gynecol Reprod Biol. 2001 May;96(1):8-20
references.pmid: 11311756
references.citation: Circulation. 2012 Feb 21;125(7):911-9
references.pmid: 22261192
references.citation: J Clin Invest. 2003 Mar;111(5):649-58
references.pmid: 12618519
references.citation: Circulation. 2015 Sep 29;132(13):1234-42
references.pmid: 26391409
references.citation: Hypertension. 2013 May;61(5):1103-10
references.pmid: 23460290
references.citation: Am J Perinatol. 2010 Sep;27(8):655-62
references.pmid: 20232280
references.citation: J Exp Med. 2008 Oct 27;205(11):2623-31
references.pmid: 18852292
references.citation: Lancet. 1994 Mar 12;343(8898):619-29
references.pmid: 7906809
references.citation: Hypertension. 2001 Apr;37(4):1191-5
references.pmid: 11304523
references.citation: J Matern Fetal Neonatal Med. 2008 Jan;21(1):9-23
references.pmid: 18175241
references.citation: Am J Physiol Renal Physiol. 2012 Sep;303(5):F783-8
references.pmid: 22696603
references.citation: Am J Epidemiol. 2015 Jun 1;181(11):861-73
references.pmid: 25947956
references.citation: Hypertension. 2015 Dec;66(6):1116-22
references.pmid: 26459420
references.citation: Physiol Rep. 2013 Sep 1;1(4):e00081
references.pmid: 24159378
references.citation: Am J Obstet Gynecol. 2016 Jan;214(1):108.e1-108.e14
references.pmid: 26432463
references.citation: Lancet Glob Health. 2014 Jun;2(6):e323-33
references.pmid: 25103301
references.citation: Hypertension. 2001 Feb;37(2 Pt 2):485-9
references.pmid: 11230323
references.citation: N Engl J Med. 2004 Feb 12;350(7):672-83
references.pmid: 14764923
references.citation: Eur J Obstet Gynecol Reprod Biol. 1996 Dec;70(1):33-9
references.pmid: 9031918
references.citation: Hypertension. 2015 Sep;66(3):687-97; discussion 445
references.pmid: 26222708
references.citation: Hypertension. 2012 Jun;59(6):1099-100
references.pmid: 22526256
references.citation: Hypertension. 2007 Dec;50(6):1142-7
references.pmid: 17923588
references.citation: Ann N Y Acad Sci. 2009 Apr;1160:381-4
references.pmid: 19416224
references.citation: Am J Health Syst Pharm. 2009 Feb 15;66(4):337-44
references.pmid: 19202042
references.citation: Exp Mol Med. 2012 Jan 31;44(1):1-9
references.pmid: 22228176
references.citation: Am J Physiol Regul Integr Comp Physiol. 2013 Jan 15;304(2):R130-5
references.pmid: 23193111
references.citation: J Am Soc Nephrol. 2014 Apr;25(4):717-25
references.pmid: 24335973
references.citation: Pregnancy Hypertens. 2012 Jul;2(3):210
references.pmid: 26105275
references.citation: Kidney Int. 2011 Jun;79(11):1254-8
references.pmid: 21368744
references.citation: Hypertension. 2008 Nov;52(5):873-80
references.pmid: 18824660
references.citation: Hypertension. 2005 Nov;46(5):1077-85
references.pmid: 16230516
references.citation: Am J Physiol Heart Circ Physiol. 2013 Apr 15;304(8):H1159-65
references.pmid: 23417865
references.citation: Am J Physiol Regul Integr Comp Physiol. 2014 Dec 1;307(11):R1353-7
references.pmid: 25298513
references.citation: Circulation. 2011 Jun 21;123(24):2856-69
references.pmid: 21690502
references.citation: Hypertension. 2003 Mar;41(3):457-62
references.pmid: 12623943