OP0011. Impaired autophagy in extravillous trophoblast may induce poor placentation in preeclampsia

Abstract

Shallow invasion of extravillous trophoblast (EVT) and inadequate vascular remodeling by EVT are the major cause of poor placentation in preeclampsia. In early pregnancy period, trophoblast experience hypoxic and low-nutrient condition. Autophagy is a cellular bulk degradation system to maintain cellular homeostasis under stress. We examined whether autophagy sustained the EVT functions under the harsh condition. An enhancement of autophagy was observed in primary cultured EVT and EVT cell line under 2% oxygen condition or cobalt treatment which induce HIF1α. The invasion and vascular remodeling under hypoxic condition were significantly reduced in autophagy-deficient EVT cells compared with wild-type EVT cells. Treatment of ATP partially rescued the poor invation under hypoxic condition suggesting that getting energy using autophagy play important role for cell invasion under hypoxia. Soluble endoglin (sENG), that is increased in sera in preeclamptic cases, suppressed EVT invasion and vascular remodeling by EVT by inhibiting autophagy. Next we have examined the impaired autophagy by immunohistochemical staining for p62. p62 is selectively degradated in autophagosome, so if impaired autophagy is present, p62 is accumulated in the cytoplasma. Enhanced imunostainings for p62 in interstitial EVT and endovascular EVT in preeclamptic cases were observed showing impaired autophagy in EVT of preeclamptic cases. sENG is known to inhibit TGFβ that is a essential factor for differentiation of regulatory T cells. Impaired autophagy and decreased regulatory T cells by increased sENG may play important roles in pathophysiology of preeclampsia.