Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice.
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.
Mizugishi
Kiyomi
K
Genetics of Development and Disease Branch, NIDDK, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
Li
Cuiling
C
Olivera
Ana
A
Bielawski
Jacek
J
Bielawska
Alicja
A
Deng
Chu-Xia
CX
Proia
Richard L
RL
D000022:Abortion, Spontaneous / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D003656:Decidua / Q000098:blood supply / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D007247:Infertility, Female / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D010714:Phosphatidylethanolamines / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D013107:Sphingolipids / Q000032:analysis / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D014599:Uterus / Q000098:blood supply / Q000737:chemistry / Q000378:metabolism*; D000099157:Sphingosine Kinase
D010714:Phosphatidylethanolamines; D017853:Phosphotransferases (Alcohol Group Acceptor); D011374:Progesterone; D013107:Sphingolipids; D013110:Sphingosine; D000099157:Sphingosine Kinase; C483858:phosphatidylethanolamine; C005682:safingol