Abstract
Alpha-1 antitrypsin (A1AT) is a glycoprotein that has been shown to protect tissues from proteolytic damage under various inflammatory conditions. Several studies show that A1AT may be associated with pre-eclampsia. However, the role of A1AT expression in placental physiology is not fully understood. In the present study, we aim to characterize the expression and function of placental A1AT. A1AT knockdown is found to reduce the expression of the serine protease HTRA1 in a trophoblast cell line. In addition, A1AT overexpression (A1AT-OE) increases the expression of HTRA1, IL6, CXCL8, and several markers of endoplasmic reticulum (ER) stress. Treatment with tunicamycin or thapsigargin, which induces ER stress, increases HTRA1 expression. Furthermore, immunohistochemistry reveals that HTRA1 is expressed in trophoblasts and the endometrial decidual cells of human placentas. An invasion assay shows that A1AT and HTRA1 stimulate cell invasion, but treatment with the ER stress inhibitors reduces the expression of HTRA1 and ER stress markers and prevents cell invasion in A1AT-OE trophoblasts. These results suggest that endogenous A1AT regulates inflammatory cytokine expression and HTRA1-induced trophoblast invasion via the induction of ER stress. It is concluded that an imbalance in the functional link between A1AT and ER stress at the maternal–fetal interface might cause abnormal placental development.
Highlights
The placenta plays a major role in feto-maternal communication and the maintenance of pregnancy
The effect of Alpha-1 antitrypsin (A1AT) knockdown (KD) or overexpression (OE) on the expression of HTRAs and the pro-inflammatory genes IL6 and CXCL8 was determined in HTR8/SVneo cells (Figure 1a,b)
As HTRA1 regulates the invasion of trophoblast cells [15], we evaluated the effect of A1AT on that invasion
Summary
The placenta plays a major role in feto-maternal communication and the maintenance of pregnancy. Mononuclear cytotrophoblasts fuse to multinucleated syncytiotrophoblasts that cover the floating chorionic villi, or differentiate into extravillous trophoblasts, which are capable of invading the endometrium and develop from anchoring villi. Impairment of trophoblast cell invasion into the endometrium causes serious complications during pregnancy, including hypertensive disorder of pregnancy (HDP), which is mainly caused by insufficient invasion by extravillous trophoblast cells. The detailed molecular mechanisms of the development of HDP and pre-eclampsia (PE). Inadequate invasion of extravillous trophoblasts into the myometrium of the uterus and inappropriate remodeling of the uterine spiral arterioles are thought to be involved in these disorders [1]. There are several mechanisms that may contribute to trophoblast dysfunction, including ischemic placenta, dysregulation of angiogenesis, and excessive oxidative stress [2]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
