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Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia

Journal Article


Abstract


  • Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator–activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.

Authors


  •   Holobotovskyy, Vasyl (external author)
  •   Chong, Yee Seng (external author)
  •   Burchell, Jennifer (external author)
  •   He, Bo (external author)
  •   Phillips, Michael (external author)
  •   Leader, Leo (external author)
  •   Murphy, Timothy (external author)
  •   Sandow, Shaun L. (external author)
  •   McKitrick, Douglas J. (external author)
  •   Charles, Adrian K. (external author)
  •   Tare, Marianne (external author)
  •   Arnolda, Leonard F.
  •   Ganss, Ruth (external author)

Publication Date


  • 2015

Citation


  • Holobotovskyy, V., Chong, Y., Burchell, J., He, B., Phillips, M., Leader, L., Murphy, T., Sandow, S. L., McKitrick, D. J., Charles, A. K., Tare, M., Arnolda, L. F. & Ganss, R. (2015). Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia. Science Translational Medicine, 7 (290), 290ra88-1-290ra88-11.

Scopus Eid


  • 2-s2.0-84930440373

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/779

Has Global Citation Frequency


Start Page


  • 290ra88-1

End Page


  • 290ra88-11

Volume


  • 7

Issue


  • 290

Place Of Publication


  • United States

Abstract


  • Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator–activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.

Authors


  •   Holobotovskyy, Vasyl (external author)
  •   Chong, Yee Seng (external author)
  •   Burchell, Jennifer (external author)
  •   He, Bo (external author)
  •   Phillips, Michael (external author)
  •   Leader, Leo (external author)
  •   Murphy, Timothy (external author)
  •   Sandow, Shaun L. (external author)
  •   McKitrick, Douglas J. (external author)
  •   Charles, Adrian K. (external author)
  •   Tare, Marianne (external author)
  •   Arnolda, Leonard F.
  •   Ganss, Ruth (external author)

Publication Date


  • 2015

Citation


  • Holobotovskyy, V., Chong, Y., Burchell, J., He, B., Phillips, M., Leader, L., Murphy, T., Sandow, S. L., McKitrick, D. J., Charles, A. K., Tare, M., Arnolda, L. F. & Ganss, R. (2015). Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia. Science Translational Medicine, 7 (290), 290ra88-1-290ra88-11.

Scopus Eid


  • 2-s2.0-84930440373

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/779

Has Global Citation Frequency


Start Page


  • 290ra88-1

End Page


  • 290ra88-11

Volume


  • 7

Issue


  • 290

Place Of Publication


  • United States