Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice

Abstract

Uterine decidualization, a process that occurs in response to embryo implantation, is critical for embryonic survival and thus is a key event for successful pregnancy. Here we show that the sphingolipid metabolic pathway is highly activated in the deciduum during pregnancy and disturbance of the pathway by disruption of sphingosine kinase (Sphk) genes causes defective decidualization with severely compromised uterine blood vessels, leading to early pregnancy loss. Sphk-deficient female mice (Sphk1 -/-Sphk2 +/-) exhibited both an enormous accumulation of dihydrosphingosine and sphingosine and a reduction in phosphatidylethanolamine levels in pregnant uteri. These mice also revealed increased cell death in decidual cells, decreased cell proliferation in undifferentiated stromal cells, and massive breakage of decidual blood vessels, leading to uterine hemorrhage and early embryonic lethality. Thus, sphingolipid metabolism regulates proper uterine decidualization and blood vessel stability. Our findings also suggest that disturbance in sphingolipid metabolism may be considered as a cause of pregnancy loss in humans. IntroductionEmbryonic implantation is a complex series of processes that establishes the connection between maternal and embryonic tissues and requires an intricate program of uterine preparation (1, 2). Very soon after implantation, which occurs in the mouse on day 4.5 postcoitum (pc) (day 0.5 - vaginal plug), endometrial stromal cells surrounding implanting blastocysts undergo dramatic transformation (decidualization), during which they proliferate and differentiate into decidual cells. Decidualization begins in the stromal region immediately surrounding the embryo (antimesometrial site). Next to the implanting blastocyst, thin, dense, avascular cell layers, called the primary decidual zone, are formed. Adjacent to the primary decidual zone, the broad secondary decidual zone is fully developed by day 6.5 pc, and is characterized by terminally differentiated decidual polyploidy with acquisition of large mono- or binucleated cells (3). The decidua provides a vascular network for nutrition and gas exchange for the developing embryo before a functional placenta is established (4). It also acts as a barrier to uncontrolled trophoblast proliferation.The sphingolipid metabolic pathway produces bioactive signaling metabolites as well as complex lipids that are utilized in membrane organization and structure. A very prominent signaling lipid is sphingosine-1-phosphate (S1P), which enhances cell survival and growth (5-8). Recent studies have demonstrated its physiologic importance in the development of the vascular and nervous system (9-12), the heart (13), and the immune system (14-16) by signaling through a family of G protein-coupled receptors designated S1P 1-5 . In contrast, 2 precursors of S1P,

Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

“…Moreover, Michaud et al (2006) measured S1P levels in forepaw tissue and found only slight decreases in SK-1-deficient mice. Recently, Mizugishi et al (2007) generated SphK1 -/-SphK2 q/-mice and investigated uterine decidualisation. When measuring S1P levels in uteri, there was no difference between wild-type and SphK1 -/-SphK2 q/-mice.…”

An update on the biology of sphingosine 1-phosphate receptors

“…5 ) ( 126 ). S1P regulates embryonic nervous system development, as the neuroepithelial layers of the developing telencephalon in S1pr1 Ϫ / Ϫ embryos have signifi cantly increased apoptosis and decreased mitosis ( 127 ). S1P 2 may also play a role in regulating neural progenitors, as postischemic administration of the S1P 2 antagonist JTE-013 or short hairpin RNA against S1P 2 signifi cantly increased progenitor migration to the ischemic region ( 128 ).…”

NKT Cells at the Maternal-Fetal Interface

“…For example, it was recently demonstrated that a number of genes involved in sphingolipid metabolism were highly upregulated in the mouse decidua, and that disruption of sphingolipid metabolism caused pregnancy loss in mice (Mizugishi et al 2007). In addition, prosaposin, an accessory molecule essential for glycosphingolipid loading onto CD1d (Kang and Cresswell 2004;Zhou et al 2004) is known to be expressed at high levels in the decidua (Sun et al 1994).…”