Abstract P641: Markers of Autophagy are Induced in Response to Placental Ischemia

Abstract

Preeclampsia is a disorder characterized by new onset hypertension during pregnancy, as well as other clinical findings such as proteinuria and edema. This disorder affects approximately five percent of pregnancies and is the leading cause of maternal and fetal morbidity. Though the origins of the disease are unclear, it is thought that placental ischemia is central to its etiology. Commonly, the uterine spiral artery fails to adequately remodel to allow for adequate blood flow to the developing fetal/placental unit, causing hypoxia and ischemia. It is well established that hypoxia can lead to endoplasmic reticulum (ER) stress in cells. When ER stress occurs, protein misfolding occurs, leading to the unfolded protein response (UPR). One process which could be important in an attempt to restore cellular homeostasis is autophagy, a specialized process of carrying defective proteins to lysosomes for degradation to prevent aggregation from occurring. There are several factors which play a role in this process, and are utilized as a marker for autophagy, notably Beclin-1 and various autophagy related genes (Atg). Though autophagy has been examined previously in cancer and numerous cardiovascular abnormalities, it is unclear whether induction of autophagy is one of the cell survival pathways activated in response to placental ischemia. Here we have examined placental tissue from term pregnant rats and rats which have undergone placental ischemia due to the reduced uterine perfusion pressure (RUPP) procedure to to determine whether autophagy pathways have been activated as part of the cell survival response during chronic ischemia. As determined by western blot, protein levels of the autophagy markers beclin (57 ± 6 A.U. vs 113 ± 16 A.U., p<0.05), Atg3 (34 ±3 A.U. vs 54 ±8 A.U., p<0.05), Atg12 (550 ± 77 A.U. vs. 1022 ± 160 A.U., p<0.05), and Atg16 (43 ± 6 A.U. vs 147 ±47 A.U., p<0.05) were all significantly increased in placental tissue in RUPP treated animals. These data, coupled with our previous studies, suggest that several cell survival pathways are activated in response to chronic placental ischemia, notably programmed cell autophagy. The importance of these pathways in survival of placental tissue and overall placental function will be the object of future study.