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  1. Evaluation Summary:

    At the very early period of pregnancy, fetal trophoblasts invade the mammalian decidua in the placenta and remodel and connect with maternal spiral arteries, which is known as an endovascular invasion. Understanding molecular and cellular pathways for endovascular invasion and pathogenesis of preeclampsia are important topics for current vascular biology and Ob/Gyn biology, making this study timely and important. This study shows for the first time a causal link for the need for VE-cadherin on trophoblasts for the invasion of these cells into the decidua and for their role in vascular remodeling. The conclusions of this paper are mostly well supported by data, but it would be sound if the authors provide the underlying molecular mechanism to support the authors' claims.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    This is an interesting and scientifically sound study, for the first time demonstrating the important role of Cdh5 expression in trophoblasts using a genetic model. The wider interest in this study relates to the potential impact of VE-cadherin's guidance role in trophoblast invasion, for preeclampsia pathogenesis.

    VE-cadherin (gene name, Cdh5) is well known for its essential role in endothelial cell-cell contacts. However, placenta trophoblasts also express Cdh5. Sung et al., explore the effect of deleting Cdh5 from trophoblasts using a Cyp19-Cre mouse model. Loss of trophoblast Cdh5 results in suppressed invasion of Cdh5- trophoblast into spiral arteries, loss of spiral artery remodeling, reduced maternal blood flow into the placenta and disturbed embryonic development. While there is no effect of Cyp19-Cre-dependent Cdh5 deletion on endothelial Cdh5 expression or blood vessel density, trophoblast density and invasion depth are markedly suppressed. As a result, embryonic development is severely disturbed. The results are appropriately controlled and the authors' conclusions are well underbuilt.

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  3. Reviewer #2 (Public Review):

    Fetal trophoblasts are known to invade the mammalian decidua in the placenta and remodel and connect with maternal spiral arteries. This paper shows that VE-cadherin on trophoblasts is needed for the invasion of trophoblasts into the decidua and for the remodeling of spiral arteries. It was shown before, that fetal trophoblasts express endothelial adhesion molecules (such as PECAM-1 and VE-cadherin) and it was shown in in vitro migration assays that blocking or genetic inactivation of VE-cadherin interfered with trophoblast invasion/migration. The current work shows that Cyp19 (cytochrome P450)-Cre driven genetic inactivation of VE-cadherin in trophoblast cells interferes with embryonic development, invasion of fetal trophoblast into the decidua, supply of the placental labyrinth region with maternal erythrocytes, smooth muscle cell association of spiral arteries (SA) and endothelial cell displacement in SA by trophoblast cells. In addition, Doppler ultrasound analysis revealed that Cyp19-Cre driven VE-cadherin gene inactivation results in placental insufficiency and fetal distress.

    The study is important since it shows for the first time a causal link for the need of VE-cadherin on trophoblasts in vivo for the invasion of these cells into the decidua and for their role in vascular remodeling. The conclusions of this paper are mostly well supported by data, but some aspects of this study need to be extended.

    1. It is not entirely clear whether the expression of Cre driven by a very small 501 bp promotor fragment of the Cyp19 gene is indeed sufficiently specific for trophoblasts in the placenta. The paper describing the generation of these Cyp19Cre mice mentions that the Cyp19 gene which encodes cytochrome P450 is expressed in various organs, among them the fetal liver. Hemorrhaging found in the E12.5 embryo could be an indication for endothelial loss of VE-cadherin in Cyp19Cre;Cdh5fl/fl embryos. Although suppl. figure 1 shows some controls for VE-cadherin staining of endothelium in the placenta of these mice, it is unclear whether this holds up for other organs.

    2. Immunofluorescence staining of the paraffin sections resulted in high quality images in figures 2 and 3, which are very instructive. However, it is difficult to display a representative overview of the whole tissue if the results are simply based on thin sections. The results could vary a lot between sections at different positions. Therefore, the study would benefit from whole mount staining of either thick vibratome sections or even larger tissue parts that went through a tissue clearing procedure. This would allow getting a more representative 3D picture of the vasculature in large parts of the placenta. In addition to providing a more representative picture of the tissue, this would also allow us to see how the trophoblast cell system connects to spiral arteries beyond single cells integrating into the endothelial cell layer of the vessel wall. While the paraffin sections indeed very nicely show how trophoblast cells integrate into spiral arteries, which looks like it could be the result of "displacement" of endothelial cells, it is unclear how this would link to a fetal trophoblast/vascular system. This question can only be answered by analyzing whole mounts.

    3. The paper does not provide any mechanistic studies that could explain how VE-cadherin on trophoblasts could support the invasion of trophoblasts into the decidua and how it could be responsible for the dissociation of smooth muscle cells from spiral arteries. It was shown before that silencing of VE-cadherin in a trophoblast cell line interfered with the invasion/migration of these cells in in vitro assays. It would be great if the present study would attempt to analyze the consequences of VE-cadherin silencing in such cells on the expression pattern of migration relevant genes in trophoblastic cells. Is collective cell migration affected or is it a defect in cell dissociation that impairs trophoblast dissemination into the decidua of the placenta?

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  4. Reviewer #3 (Public Review):

    During pregnancy, fetal trophoblasts invade the maternal decidua and remodel spiral arteries to bring maternal blood into the placenta. This process, known as endovascular invasion, is thought to involve the adoption of functional characteristics of vascular endothelial cells (ECs) by trophoblasts through a process termed vascular mimicry. Invasive trophoblasts in preeclamptic placentas lack VE-cadherin, and loss of VE-cadherin reduces trophoblast invasion in vitro, suggesting the critical roles for VE-cadherin in endovascular invasion and vessel formation. Based on the findings, the authors claim a non-endothelial role for VE-cadherin in trophoblasts during placental development and suggest that endothelial proteins may play functionally unique roles in trophoblasts that do not simply mimic those in ECs. Overall, the data are analyzed thoroughly and the conclusions drawn are novel and appealing. Understanding molecular and cellular pathways for endovascular invasion and pathogenesis of preeclampsia are important topics for current vascular biology and Ob/Gyn biology, making this study timely and important. It would be constructive if the authors provide the underlying molecular mechanism.

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