Excess LIGHT contributes to placental impairment, increased secretion of vasoactive factors, hypertension, and proteinuria in preeclampsia

Wei Wang, Nicholas F. Parchim, Takayuki Iriyama, Renna Luo, Cheng Zhao, Chen Liu, Roxanna A. Irani, Weiru Zhang, Chen Ning, Yujin Zhang, Sean C. Blackwell, Lieping Chen, Lijian Tao, M. John Hicks, Rodney E. Kellems, Yang Xia

Research output: Contribution to journalArticle

Abstract

Preeclampsia, a prevalent hypertensive disorder of pregnancy, is believed to be secondary to uteroplacental ischemia. Accumulating evidence indicates that hypoxia-independent mediators, including inflammatory cytokines and growth factors, are associated with preeclampsia, but it is unclear whether these signals directly contribute to placental damage and disease development in vivo. We report that LIGHT, a novel tumor necrosis factor superfamily member, is significantly elevated in the circulation and placentas of preeclamptic women compared with normotensive pregnant women. Injection of LIGHT into pregnant mice induced placental apoptosis, small fetuses, and key features of preeclampsia, hypertension and proteinuria. Mechanistically, using neutralizing antibodies specific for LIGHT receptors, we found that LIGHT receptors herpes virus entry mediator and lymphotoxin β receptor are required for LIGHT-induced placental impairment, small fetuses, and preeclampsia features in pregnant mice. Accordingly, we further revealed that LIGHT functions through these 2 receptors to induce secretion of soluble fms-like tyrosine kinase-1 and endothelin-1, 2 well-accepted pathogenic factors in preeclampsia, and thereby plays an important role in hypertension and proteinuria in pregnant mice. Lastly, we extended our animal findings to human studies and demonstrated that activation of LIGHT receptors resulted in increased apoptosis and elevation of soluble fms-like tyrosine kinase-1 secretion in human placental villous explants. Overall, our human and mouse studies show that LIGHT signaling is a previously unrecognized pathway responsible for placental apoptosis, elevated secretion of vasoactive factors, and subsequent maternal features of preeclampsia, and reveal new therapeutic opportunities for the management of the disease.

Original languageEnglish (US)
Pages (from-to)595-606
Number of pages12
JournalHypertension
Volume63
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

Fingerprint

Pre-Eclampsia
Proteinuria
Hypertension
Light
Vascular Endothelial Growth Factor Receptor-1
Apoptosis
Placenta Diseases
Fetus
Endothelin-2
Lymphotoxin-alpha
Virus Internalization
Endothelin-1
Disease Management
Neutralizing Antibodies
Placenta
Pregnant Women
Intercellular Signaling Peptides and Proteins
Ischemia
Tumor Necrosis Factor-alpha
Mothers

Keywords

  • endothelin-1
  • herpes virus entry mediator
  • lymphotoxin-beta receptor
  • preeclampsia
  • receptors, tumor necrosis factor, member 14
  • tumor necrosis factor ligand superfamily member 14

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Excess LIGHT contributes to placental impairment, increased secretion of vasoactive factors, hypertension, and proteinuria in preeclampsia. / Wang, Wei; Parchim, Nicholas F.; Iriyama, Takayuki; Luo, Renna; Zhao, Cheng; Liu, Chen; Irani, Roxanna A.; Zhang, Weiru; Ning, Chen; Zhang, Yujin; Blackwell, Sean C.; Chen, Lieping; Tao, Lijian; Hicks, M. John; Kellems, Rodney E.; Xia, Yang.

In: Hypertension, Vol. 63, No. 3, 03.2014, p. 595-606.

Research output: Contribution to journalArticle

Wang, W, Parchim, NF, Iriyama, T, Luo, R, Zhao, C, Liu, C, Irani, RA, Zhang, W, Ning, C, Zhang, Y, Blackwell, SC, Chen, L, Tao, L, Hicks, MJ, Kellems, RE & Xia, Y 2014, 'Excess LIGHT contributes to placental impairment, increased secretion of vasoactive factors, hypertension, and proteinuria in preeclampsia', Hypertension, vol. 63, no. 3, pp. 595-606. https://doi.org/10.1161/HYPERTENSIONAHA.113.02458
Wang, Wei ; Parchim, Nicholas F. ; Iriyama, Takayuki ; Luo, Renna ; Zhao, Cheng ; Liu, Chen ; Irani, Roxanna A. ; Zhang, Weiru ; Ning, Chen ; Zhang, Yujin ; Blackwell, Sean C. ; Chen, Lieping ; Tao, Lijian ; Hicks, M. John ; Kellems, Rodney E. ; Xia, Yang. / Excess LIGHT contributes to placental impairment, increased secretion of vasoactive factors, hypertension, and proteinuria in preeclampsia. In: Hypertension. 2014 ; Vol. 63, No. 3. pp. 595-606.
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abstract = "Preeclampsia, a prevalent hypertensive disorder of pregnancy, is believed to be secondary to uteroplacental ischemia. Accumulating evidence indicates that hypoxia-independent mediators, including inflammatory cytokines and growth factors, are associated with preeclampsia, but it is unclear whether these signals directly contribute to placental damage and disease development in vivo. We report that LIGHT, a novel tumor necrosis factor superfamily member, is significantly elevated in the circulation and placentas of preeclamptic women compared with normotensive pregnant women. Injection of LIGHT into pregnant mice induced placental apoptosis, small fetuses, and key features of preeclampsia, hypertension and proteinuria. Mechanistically, using neutralizing antibodies specific for LIGHT receptors, we found that LIGHT receptors herpes virus entry mediator and lymphotoxin β receptor are required for LIGHT-induced placental impairment, small fetuses, and preeclampsia features in pregnant mice. Accordingly, we further revealed that LIGHT functions through these 2 receptors to induce secretion of soluble fms-like tyrosine kinase-1 and endothelin-1, 2 well-accepted pathogenic factors in preeclampsia, and thereby plays an important role in hypertension and proteinuria in pregnant mice. Lastly, we extended our animal findings to human studies and demonstrated that activation of LIGHT receptors resulted in increased apoptosis and elevation of soluble fms-like tyrosine kinase-1 secretion in human placental villous explants. Overall, our human and mouse studies show that LIGHT signaling is a previously unrecognized pathway responsible for placental apoptosis, elevated secretion of vasoactive factors, and subsequent maternal features of preeclampsia, and reveal new therapeutic opportunities for the management of the disease.",
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AU - Wang, Wei

AU - Parchim, Nicholas F.

AU - Iriyama, Takayuki

AU - Luo, Renna

AU - Zhao, Cheng

AU - Liu, Chen

AU - Irani, Roxanna A.

AU - Zhang, Weiru

AU - Ning, Chen

AU - Zhang, Yujin

AU - Blackwell, Sean C.

AU - Chen, Lieping

AU - Tao, Lijian

AU - Hicks, M. John

AU - Kellems, Rodney E.

AU - Xia, Yang

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