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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Epidermal growth factor and sphingosine-1-phosphate stimulate Na⁺/H⁺ exchanger activity in the human placental syncytiotrophoblast

Maternal and Fetal Health Research Group, The Medical School, University of Manchester, St. Mary's Hospital, Manchester, United Kingdom

Submitted 10 May 2007 ; accepted in final form 30 September 2007

The Na⁺/H⁺ exchanger (NHE) has a key role in intracellular pH ([pH]_i) regulation of the syncytiotrophoblast in the human placenta and may have a role in the life cycle of this cell. In other cells the NHE (actually a family of up to 9 isoforms) is regulated by a variety of factors, but its regulation in the syncytiotrophoblast has not been studied. Here, we tested the hypotheses that EGF and sphingosine-1-phosphate (S1P), both of which affect trophoblast apoptosis and, in other cell types, NHE activity, stimulate syncytiotrophoblast NHE activity. Villous fragments from term human placentas were loaded with the pH-sensitive dye, BCECF. NHE activity was measured by following the recovery of syncytiotrophoblast [pH]_i following an imposed acid load, in the presence and absence of EGF, S1P, and specific inhibitors of NHE activity. Both EGF and S1P caused a dose-dependent upregulation of NHE activity in the syncytiotrophoblast. These effects were blocked by amiloride 500 µM (a nonspecific NHE blocker) and HOE694 100 µM (NHE blocker with NHE1 and 2 isoform selectivity). Effects of EGF were also reduced by the NHE3 selective blocker S3226 (used at 1 µM). These data provide the first evidence that both EGF and S1P stimulate NHE activity in the syncytiotrophoblast; they appear to do so predominantly by activating the NHE1 isoform.

epidermal growth factor; sphingosine-1-phosphate; Na⁺/H⁺ exchanger; placenta; apoptosis

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