Down-Regulation of Growth Signaling Pathways Linked to a Reduced Cotyledonary Vascularity in Placentomes of Over-Nourished, Obese Pregnant Ewes

Zhu, M.J.; Du, M.; Nijland, M.J.; Nathanielsz, P.W.; Hess, B.W.; Moss, G.E.; Ford, S.P.

doi:10.1016/j.placenta.2009.02.001

« Previous Next »Placenta
Volume 30, Issue 5 , Pages 405-410, May 2009

Down-Regulation of Growth Signaling Pathways Linked to a Reduced Cotyledonary Vascularity in Placentomes of Over-Nourished, Obese Pregnant Ewes

M.J. Zhu
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, 1000E University Avenue, Laramie, WY 82071, USA
M. Du
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, 1000E University Avenue, Laramie, WY 82071, USA
M.J. Nijland
- Center for Pregnancy and Newborn Research, University of Texas, Health Sciences Center, San Antonio, TX 78229, USA
P.W. Nathanielsz
- Center for Pregnancy and Newborn Research, University of Texas, Health Sciences Center, San Antonio, TX 78229, USA
B.W. Hess
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, 1000E University Avenue, Laramie, WY 82071, USA
G.E. Moss
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, 1000E University Avenue, Laramie, WY 82071, USA
S.P. Ford
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, 1000E University Avenue, Laramie, WY 82071, USA
- Corresponding author. Tel.: +1 307 766 2709; fax: +1 307 766 2355.

Accepted 7 February 2009. published online 09 March 2009.

Abstract

Both protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) are down-stream components of the insulin/insulin like growth factor-1 (IGF-1) signaling pathway. AMP-activated protein kinase (AMPK) is known to sensitize cells to insulin/IGF-1 signaling. The objective of this study was to assess the activity of AMPK and its role in the observed down-regulation of insulin/IGF-1 signaling in cotyledonary (COT) arteries supplying the placental component of the ewe placentome. Nonpregnant ewes were randomly assigned to a control (C, 100% of NRC recommendations) or obesogenic (OB, 150% of NRC) diet from 60 days before conception until necropsy on day 75 of gestation (n=5/group) or until lambing (n=5/group). At necropsy on day 75 of gestation, the smallest terminal arteries that entered the COT tissues (0.5–1.0mm in diameter) were collected for analyses. Fetal weights were ∼20% greater (P<0.05) on OB than C ewes, but birth weights of lambs were similar across dietary groups. Fetal plasma concentrations of glucose, insulin and IGF-1 were higher (P<0.05) in the blood of fetuses from OB than C ewes. Total AMPK and phosphorylated AMPK at Thr 172 (the active form) were reduced (P<0.05) by 19.7±8.4% and 25.9±7.7%, respectively in the COT arterial tissues of OB ewes. Total acetyl-CoA carboxylase (ACC), a down-stream target of AMPK, and its phosphorylated form were also reduced (P<0.05) by 32.9±9.2% and 45.4±14.6%, respectively. The phosphorylation of IRS-1 at Ser 789, a site phosphorylated by AMPK, was 24.5±9.0% lower (P<0.05) in COT arteries of OB than C ewes. No alteration in total insulin receptor, total IGF-1 receptor or their phosphorylated forms was observed, down-stream insulin signaling was down-regulated in COT arteries of OB ewes, which may have resulted in the observed decrease in COT vascular development in OB ewes.