Placental Growth Factor Reduces Blood Pressure in a Uteroplacental Ischemia Model of Preeclampsia in Nonhuman Primates.
An imbalance in the angiogenesis axis during pregnancy manifests as clinical preeclampsia because of endothelial dysfunction. Circulating soluble fms-like tyrosine kinase 1 (sFLT-1) increases and placental growth factor (PlGF) reduces before and during disease. We investigated the clinical and biochemical effects of replenishing the reduced circulating PlGF with recombinant human PlGF (rhPlGF) and thus restoring the angiogenic balance. Hypertensive proteinuria was induced in a nonhuman primate (Papio hamadryas) by uterine artery ligation at 136 days gestation (of a 182-day pregnancy). Two weeks after uteroplacental ischemia, rhPlGF (rhPlGF, n=3) or normal saline (control, n=4) was administered by subcutaneous injection (100 μg/kg per day) for 5 days. Blood pressure was monitored by intra-arterial radiotelemetry and sFLT-1 and PlGF by ELISA. Uteroplacental ischemia resulted in experimental preeclampsia evidenced by increased blood pressure, proteinuria, and endotheliosis on renal biopsy and elevated sFLT-1. PlGF significantly reduced after uteroplacental ischemia. rhPlGF reduced systolic blood pressure in the treated group (-5.2±0.8 mm Hg; from 132.6±6.6 mm Hg to 124.1±7.6 mm Hg) compared with an increase in systolic blood pressure in controls (6.5±3 mm Hg; from 131.3±1.5 mm Hg to 138.6±1.5 mm Hg). Proteinuria reduced in the treated group (-72.7±55.7 mg/mmol) but increased in the control group. Circulating levels of total sFLT-1 were not affected by the administration of PlGF; however, a reduction in placental sFLT-1 mRNA expression was demonstrated. There was no significant difference between the weights or lengths of the neonates in the rhPlGF or control group; however, this study was not designed to assess fetal safety or outcomes. Increasing circulating PlGF by the administration of rhPlGF improves clinical parameters in a primate animal model of experimental preeclampsia.
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.). angela.makris@sswahs.nsw.gov.au.
Angela
A
Makris
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Kristen R
KR
Yeung
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Shirlene M
SM
Lim
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Neroli
N
Sunderland
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Scott
S
Heffernan
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
John F
JF
Thompson
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Jim
J
Iliopoulos
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Murray C
MC
Killingsworth
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Jim
J
Yong
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Bei
B
Xu
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Robert F
RF
Ogle
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Ravi
R
Thadhani
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
S Ananth
SA
Karumanchi
From the Medicine Faculty, Western Sydney University and Ingham Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., J.I., M.C.K., B.X., A.H.); Medicine Faculty, University of New South Wales, Sydney, NSW, Australia (A.M., M.C.K., J.Y.); Nephrology Department, Liverpool Hospital, Liverpool, NSW, Australia (A.M., J.I.); Vascular Immunology Group, Heart Research Institute, Sydney, NSW, Australia (A.M., K.R.Y., S.M.L., B.X., A.H.); Nephrology Department (N.S., S.H.), Melanoma Unit (J.F.T.), and Obstetrics Department (R.F.O.), Royal Prince Alfred Hospital, Sydney, NSW, Australia; Department of Surgery, University of Sydney, Sydney, NSW, Australia (J.F.T.); Anatomical Pathology Department (M.C.K., J.Y.) and Vascular Surgery Department (J.I.), Liverpool Hospital, Liverpool, NSW, Australia; Division of Nephrology, Massachusetts General Hospital, Boston (R.T.); and Centre for Vascular Biology, Beth Israel Deaconess Medical Centre, Boston, MA (S.A.K.).
Annemarie
A
Hennessy
D000818:Animals; D001795:Blood Pressure Determination; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D046110:Hypertension, Pregnancy-Induced / Q000188:drug therapy* / Q000473:pathology; D007511:Ischemia / Q000188:drug therapy / Q000503:physiopathology; D010215:Papio; D010920:Placenta / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D000072483:Placenta Growth Factor / Q000494:pharmacology*; D016133:Polymerase Chain Reaction / Q000379:methods; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000473:pathology; D011247:Pregnancy; D011270:Pregnancy, Animal; D011897:Random Allocation; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D000072483:Placenta Growth Factor
animal model; hypertension; placental growth factor; preeclampsia/pregnancy