Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice
Kiyomi Mizugishi, Cuiling Li, Ana Olivera, Jacek Bielawski, Alicja Bielawska, Chu-Xia Deng, Richard L. Proia
Kiyomi Mizugishi, Cuiling Li, Ana Olivera, Jacek Bielawski, Alicja Bielawska, Chu-Xia Deng, Richard L. Proia
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Research Article Reproductive biology

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.

Authors

Kiyomi Mizugishi, Cuiling Li, Ana Olivera, Jacek Bielawski, Alicja Bielawska, Chu-Xia Deng, Richard L. Proia

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Figure 1

Normal ovarian functions and implantation in Sphk1–/–Sphk2+/– female mice.

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Normal ovarian functions and implantation in Sphk1–/–Sphk2+/– female mic...
(A) Representative photographs of H&E staining of ovaries (n = 3). (B) Serum P4 levels on day 6.5 pc, day 7.5 pc, day 8.5 pc, and day 11.5 pc (n = 3). (C–E) Measurement of Sphk activity in ovariectomized wild-type females. The mice were given a single injection of E2 (100 ng/mouse), a single injection of P4 (2 mg/mouse), or E2 plus P4, and sacrificed 6 hours or 12 hours later (C and D). Another group of mice received a regimen designed to mimic the P4 and E2 levels during the estrous cycle and early pregnancy described in Methods (E). The assay was performed in the presence of Triton X-100 (C and E) or of BSA complexes without Triton X-100 (D and E). The data represent mean values ± SE (n = 3, *P < 0.01, paired Student’s t test). (F) Ovulation and fertilization rates on day 1.5 pc. Results of ovulation are mean values ± SE. n = 4 (wild-type), n = 3 (Sphk1–/–Sphk2+/–), unpaired Student’s t test. (G) Representative photographs of uteri with implantation sites (blue bands) on day 5.5 pc. Arrows indicate implantation sites. (H) The number and weight of implantation sites were examined on day 5.5 pc by the blue dye method. The data represent mean values ± SE. n = 3 (wild-type); n = 5 (Sphk1–/–Sphk2+/–); unpaired Student’s t test. Scale bars: 200 μm (A); 1 mm (G).