Abstract
During placenta development, a succession of complex molecular and cellular interactions between the maternal endometrium and the developing embryo ensures reproductive success. The precise mechanisms regulating this maternal-fetal crosstalk remain unknown. Our study revealed that the expression of Rac1, a member of the Rho family of GTPases, is markedly elevated in mouse decidua on days 7 and 8 of gestation. To investigate its function in the uterus, we created mice bearing a conditional deletion of the Rac1 gene in uterine stromal cells. Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage. To gain insights into the molecular pathways affected by the loss of Rac1, we performed gene expression profiling which revealed that Rac1 signaling regulates the expression of Rab27b, another GTPase that plays a key role in targeting vesicular trafficking. Consequently, the Rac1-null decidual cells failed to secrete vascular endothelial growth factor A, which is a critical regulator of decidual angiogenesis, and insulin-like growth factor binding protein 4, which regulates the bioavailability of insulin-like growth factors that promote proliferation and differentiation of trophoblast cell lineages in the ectoplacental cone. The lack of secretion of these key factors by Rac1-null decidua gave rise to impaired angiogenesis and dysregulated proliferation of trophoblast cells, which in turn results in overexpansion of the trophoblast giant cell lineage and disorganized placenta development. Further experiments revealed that RAC1, the human ortholog of Rac1, regulates the secretory activity of human endometrial stromal cells during decidualization, supporting the concept that this signaling G protein plays a central and conserved role in controlling endometrial secretory function. This study provides unique insights into the molecular mechanisms regulating endometrial secretions that mediate stromal-endothelial and stromal-trophoblast crosstalk critical for placenta development and establishment of pregnancy.
Highlights
After fertilization, the uterus transitions to a receptive state that allows embryo attachment and invasion, and this process must be synchronized with embryonic development in order to ensure maximal reproductive success [1,2,3,4,5]
In the absence of related C3 botulinum toxin substrate 1 (Rac1), the expression of Rab27b, another G protein that plays a key role in vesicular exocytosis [17, 18], is markedly impaired in the decidual cells. Consistent with this finding, our studies revealed that the Rac1-null decidual cells exhibit a defect in the secretion of vascular endothelial growth factor A (VEGFA) and insulin-like growth factor binding protein 4 (IGFBP4)
Because of the vascular defect and hemorrhage in Rac1d/d uteri, we focused on the angiogenesis-related pathways and found several factors, including angiopoietin 2 (Angpt2), neuropilin 1 (Nrp1), sphingosine kinase 1 (Sphk1), and Epas1/Hif2α, which were downregulated in Rac1d/d uteri compared to Rac1f/f uteri as early as day 8 of pregnancy (S1 Table)
Summary
The uterus transitions to a receptive state that allows embryo attachment and invasion, and this process must be synchronized with embryonic development in order to ensure maximal reproductive success [1,2,3,4,5]. To enable this synchronization, an intricate maternal-fetal dialogue has evolved that allows the developing embryo and the uterus to be in constant communication with each other. The current challenge is to understand the complex processes by which various signaling molecules emanating from the maternal decidua communicate with trophoblasts to ensure successful establishment and maintenance of pregnancy
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