Insulin restores l-arginine transport requiring adenosine receptors activation in umbilical vein endothelium from late-onset preeclampsia

• Late-onset preeclampsia associates with foetoplacental endothelial dysfunction.
• Insulin restores late-onset preeclampsia – reduced umbilical vein relaxation.
• Insulin beneficial effect requires A2AAR activation in late-onset preeclampsia.

IntroductionPreeclampsia is associated with impaired placental vasodilation and reduced endothelial nitric oxide synthase (eNOS) activity in the foetoplacental circulation. Adenosine and insulin stimulate vasodilation in endothelial cells, and this activity is mediated by adenosine receptor activation in uncomplicated pregnancies; however, this activity has yet to be examined in preeclampsia. Early onset preeclampsia is associated with severe placental vasculature alterations that lead to altered foetus growth and development, but whether late-onset preeclampsia (LOPE) alters foetoplacental vascular function is unknown.MethodsVascular reactivity to insulin (0.1–1000 nmol/L, 5 min) and adenosine (1 mmol/L, 5 min) was measured in KCl-preconstricted human umbilical vein rings from normal and LOPE pregnancies using a wire myograph. The protein levels of human cationic amino acid transporter 1 (hCAT-1), adenosine receptor subtypes, total and Ser1177-or Thr495-phosphorylated eNOS were detected via Western blot, and l-arginine transport (0–1000 μmol/L l-arginine, 3 μCi/mL L-[3H]arginine, 20 s, 37 °C) was measured in the presence or absence of insulin and adenosine receptor agonists or antagonists in human umbilical vein endothelial cells (HUVECs) from normal and LOPE pregnancies.ResultsLOPE increased the maximal l-arginine transport capacity and hCAT-1 and eNOS expression and activity compared with normal conditions. The A2A adenosine receptor (A2AAR) antagonist ZM-241385 blocked these effects of LOPE. Insulin-mediated umbilical vein ring relaxation was lower in LOPE pregnancies than in normal pregnancies and was restored using the A2AAR antagonist.Discussion and conclusionsThe reduced foetoplacental vascular response to insulin may result from A2AAR activation in LOPE pregnancies.

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