RESUMO
Maternal hypertension during pregnancy is a major risk factor for intrauterine growth restriction (IUGR), which increases susceptibility to cardiovascular and metabolic disease in adulthood through unclear mechanisms. The aim of this study was to characterize the pancreatic ß-cell area and function in the fetal rat offspring of a reduced uterine perfusion pressure (RUPP) model of gestational hypertension. At embryonic day 19.5, RUPP dams exhibited lower body weight, elevated mean blood pressure, reduced litter size, and higher blood glucose compared with sham-operated controls. In RUPP placental lysates, a nonsignificant change in mammalian target of rapamycin (mTOR) activity markers, phosphorylated S6 at serine 240, and phosphorylated AKT (at S473) was observed. RUPP offspring showed significantly reduced ß-cell-to-pancreas area and increased ß-cell death but normal insulin levels in serum. Isolated islets had normal insulin content and secretory function in response to glucose and palmitate. Fetal pancreatic lysates showed a tendency for reduced insulin levels, with a significant reduction in total mTOR protein with RUPP surgery. In addition, its downstream complex 2 targets phosphorylation of AKT at S473, and pAKT at Thr308 tended to be reduced in the fetal RUPP pancreas. Altogether, these data show that RUPP offspring demonstrated increased ß-cell death, reduced ß-cell area, and altered nutrient-sensor mTOR protein level in the pancreas. This could represent a mechanistic foundation in IUGR offspring's risk for enhanced susceptibility to type 2 diabetes and other metabolic vulnerabilities seen in adulthood.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Placenta/metabolismo , Útero/irrigação sanguínea , Animais , Pressão Sanguínea/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Ratos Sprague-DawleyRESUMO
Preeclampsia is a pregnancy-specific condition manifested by new-onset maternal hypertension with systemic inflammation, including increased innate immune system complement activation. While exact pathophysiology is unknown, evidence suggests that inadequate spiral artery invasion and resulting utero-placental insufficiency is the initiating event. Cigarette smoking during pregnancy decreases the risk of preeclampsia. Nicotine, a major component of cigarettes, stimulates the efferent cholinergic anti-inflammatory pathway through peripherally expressed nicotinic acetylcholine receptors (nAChR) and is known to attenuate ischemia-reperfusion injury in kidney and liver. Prior studies indicated that complement activation was critical for placental ischemia-induced hypertension in a rat model. Thus, it was hypothesized here that nicotine was responsible for the protective effect of cigarette smoking in preeclampsia and would attenuate placental ischemia-induced systemic complement activation and hypertension. The Reduced Utero-placental Perfusion Pressure (RUPP) model in the pregnant rat was employed to induce placental ischemia, resulting in complement activation, fetal resorptions, and hypertension. On gestation day (GD)14, nicotine (1 mg/kg) or saline was administered via subcutaneous injection prior to RUPP surgery and daily through GD18. On GD19, placental ischemia significantly increased mean arterial pressure (MAP) in saline injected animals. However, the placental ischemia-induced increase in blood pressure was not evident in nicotine-treated animals and nicotine treatment significantly increased MAP variability. Circulating C3a was measured as an indicator of complement activation and increased C3a in RUPP compared to Sham persisted with nicotine treatment, as did fetal resorptions. These data suggested to us that nicotine may contribute to the decreased risk of preeclampsia with cigarette smoking, but this protective effect was confounded by additional effects of nicotine on the cardiovascular system.