Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in nonhuman primates

Angela Makris, Kristen R. Yeung, Shirlene M. Lim, Neroli Sunderland, Scott Heffernan, John F. Thompson, Jim Iliopoulos, Murray C. Killingsworth, Jim Yong, Bei Xu, Robert F. Ogle, Ravi Thadhani, S. Ananth Karumanchi, Annemarie Hennessy

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

LanguageEnglish
Pages1263-1272
Number of pages10
JournalHypertension
Volume67
Issue number6
DOIs
Publication statusPublished - Jun 2016
Externally publishedYes

Keywords

  • animal model
  • hypertension
  • placental growth factor
  • preeclampsia/pregnancy

Cite this

Makris, Angela ; Yeung, Kristen R. ; Lim, Shirlene M. ; Sunderland, Neroli ; Heffernan, Scott ; Thompson, John F. ; Iliopoulos, Jim ; Killingsworth, Murray C. ; Yong, Jim ; Xu, Bei ; Ogle, Robert F. ; Thadhani, Ravi ; Karumanchi, S. Ananth ; Hennessy, Annemarie. / Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in nonhuman primates. In: Hypertension. 2016 ; Vol. 67, No. 6. pp. 1263-1272.
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title = "Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in nonhuman primates",
abstract = "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.",
keywords = "animal model, hypertension, placental growth factor, preeclampsia/pregnancy",
author = "Angela Makris and Yeung, {Kristen R.} and Lim, {Shirlene M.} and Neroli Sunderland and Scott Heffernan and Thompson, {John F.} and Jim Iliopoulos and Killingsworth, {Murray C.} and Jim Yong and Bei Xu and Ogle, {Robert F.} and Ravi Thadhani and Karumanchi, {S. Ananth} and Annemarie Hennessy",
year = "2016",
month = "6",
doi = "10.1161/HYPERTENSIONAHA.116.07286",
language = "English",
volume = "67",
pages = "1263--1272",
journal = "Hypertension",
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Makris, A, Yeung, KR, Lim, SM, Sunderland, N, Heffernan, S, Thompson, JF, Iliopoulos, J, Killingsworth, MC, Yong, J, Xu, B, Ogle, RF, Thadhani, R, Karumanchi, SA & Hennessy, A 2016, 'Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in nonhuman primates' Hypertension, vol. 67, no. 6, pp. 1263-1272. https://doi.org/10.1161/HYPERTENSIONAHA.116.07286

Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in nonhuman primates. / Makris, Angela; Yeung, Kristen R.; Lim, Shirlene M.; Sunderland, Neroli; Heffernan, Scott; Thompson, John F.; Iliopoulos, Jim; Killingsworth, Murray C.; Yong, Jim; Xu, Bei; Ogle, Robert F.; Thadhani, Ravi; Karumanchi, S. Ananth; Hennessy, Annemarie.

In: Hypertension, Vol. 67, No. 6, 06.2016, p. 1263-1272.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in nonhuman primates

AU - Makris,Angela

AU - Yeung,Kristen R.

AU - Lim,Shirlene M.

AU - Sunderland,Neroli

AU - Heffernan,Scott

AU - Thompson,John F.

AU - Iliopoulos,Jim

AU - Killingsworth,Murray C.

AU - Yong,Jim

AU - Xu,Bei

AU - Ogle,Robert F.

AU - Thadhani,Ravi

AU - Karumanchi,S. Ananth

AU - Hennessy,Annemarie

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N2 - 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.

AB - 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.

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