Endothelial Jagged1 Antagonizes Dll4/Notch Signaling in Decidual Angiogenesis during Early Mouse Pregnancy
<p>Characterization of the E7.5 uterine vasculature in wildtype mice. (<b>A</b>) Schematic representation of an E7.5 implantation site (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>). The implantation site is divided (represented by the dashed line) into two regions, the anti-mesometrial region (AMR) and the mesometrial region (MR), which is further divided into the mesometrial pole (MP) and central region (CTR). Labeled are spiral arteries (white ellipses) in the MP, capillaries (white rectangles) in the CTR, capillaries (red rectangles) in the AMR and the embryo (e). (<b>B</b>) H&E of an implantation site at E7.5 showing the embryo and central parts of the decidua. (<b>C</b>) An E7.5 implantation site double stained for the endothelial cell marker, CD31 and pericyte marker, NG2. Ellipses identify NG2<sup>+</sup> SpAs at the MP. Rectangles identify CD31<sup>+</sup> capillaries in the central region (white rectangle) and the AMR (red rectangle). (<b>D</b>–<b>F</b>) High magnification images of the vessels of the MR at the MP and CTR and AMR. Sections were double stained to detect expression of CD31 and mural cell markers, NG2, PDGFRβ or SMA. Merged images are outlined in yellow. CD31<sup>+</sup> endothelial cells (ECs) are present throughout the implantation site in all three regions. (<b>D</b>) The vasculature in the MP is composed of SpAs seen as CD31<sup>+</sup> ECs covered by NG2<sup>+</sup>, PDGFRβ<sup>+</sup> and SMA<sup>+</sup> mural cells (white arrowheads) and capillaries comprised of ECs that are not associated with NG2, PDGFRβ or SMA (yellow rectangles). NG2 and PDGFRβ are co-expressed (white arrow). (<b>E</b>) In the CTR, expression of NG2 is sparse and expression of PDGFRβ was not detected. Few CD31<sup>+</sup> capillaries are associated with NG2<sup>+</sup> mural cells (white arrowhead). (<b>F</b>) In the AMR, capillaries are comprised of CD31<sup>+</sup> ECs closely associated with NG2<sup>+</sup>/PDGFRβ<sup>+</sup> mural cells (white arrowheads). Scale bars = 200 μm in (<b>B</b>,<b>C</b>) and 50 μm in (<b>D</b>–<b>F</b>).</p> "> Figure 2
<p>Expression of receptors, Notch1 and Notch4, in the E7.5 decidual vasculature. High magnification images of sections double stained to detect expression of Notch1 or Notch4 and the endothelial cell marker, CD31 or mural cell marker, PDGFRββ. Merged images are outlined in yellow. (<b>A</b>) In the MP, Notch1 and Notch4 are expressed in CD31<sup>+</sup> SpA ECs (white arrows). PDGFRβ<sup>+</sup> mural cells are associated with both Notch1<sup>+</sup> and Notch4<sup>+</sup> ECs in the SpAs (white arrowheads). (<b>B</b>) In the CTR, CD31<sup>+</sup> capillary ECs express Notch1 and Notch4 (white arrows). (<b>C</b>) In the AMR, CD31<sup>+</sup> capillary ECs express Notch1 (white arrows) and PDGFRβ<sup>+</sup> pericytes are associated with Notch1<sup>+</sup> cells (white arrowhead). AMR = anti-mesometrial; CTR = central region; MP = mesometrial pole. Scale bars = 50 μm.</p> "> Figure 3
<p>Expression of Notch ligands, Jag1 and Dll4, in the E7.5 decidual vasculature. High magnification images of sections double stained to detect expression of Jag1 or Dll4 and the endothelial cell marker, CD31 or mural cell marker, PDGFRβ. (<b>A</b>) In MP SpAs, Jag1 is expressed in CD31<sup>+</sup> ECs (white arrow) and in NG2<sup>+</sup> and PDGFRβ<sup>+</sup> mural cells (white arrows). Some Jag1<sup>+</sup> ECs are closely associated with PDGFRβ<sup>+</sup>/Jag1<sup>−</sup> mural cells (white arrowheads). (<b>B</b>) Expression of Jag1 is not detected in the central region. (<b>C</b>) In the AMR, expression of Jag1 is sparse. Jag1 is expressed in CD31<sup>+</sup> ECs and PDGFRβ<sup>+</sup> mural cells (white arrows). Jag1<sup>+</sup> cells are closely associated with PDGFRβ<sup>+</sup> mural cells (white arrowheads). (<b>D</b>) In MP SpAs, Dll4 is expressed in CD31<sup>+</sup> ECs (white arrows). NG2<sup>+</sup> and PDGFRβ<sup>+</sup> mural cells are closely associated with Dll4<sup>+</sup> cells (white arrowheads). (<b>E</b>) In the CTR, Dll4 is expressed in a punctate pattern (white arrowheads). (<b>F</b>) In the AMR, Dll4 is expressed in CD31<sup>+</sup> ECs (white arrows). Dll4<sup>+</sup> cells are associated with PDGFRβ<sup>+</sup> mural cells (white arowheads). AMR = anti-mesometrial; CTR = central region; MP = mesometrial pole. Scale bars = 50 μm.</p> "> Figure 4
<p>Tamoxifen-induced Cre recombination decreases expression of Jag1 in <span class="html-italic">Cdh5-Cre<sup>ERT2</sup>;Jag1<sup>flox/flox</sup></span> (<span class="html-italic">Jag1ΔEC</span>) pregnancy. (<b>A</b>) Schematic of the mouse gestation timeline highlighting key processes involved, and experimental timeline (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>). At E4.5, tamoxifen is administered to induce Cre recombination and progesterone was administered to minimize secondary angiogenic defects in the uterus due to vascular defects in the ovaries. Pregnancies and uterine phenotype were assessed at E7.5. (<b>B</b>) Representative image of an implantation site at E7.5 from the <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span>; <span class="html-italic">ROSA26 tdTomato</span> reporter. The decidua is within the dashed white. tdTomato expression, indicating Cre-induced recombination, is detected in a vascular pattern throughout the decidua. Dashed line denotes MR and AMR. (<b>C</b>,<b>D</b>) Representative images of implantation sites of <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> control and <span class="html-italic">Jag1ΔEC</span> pregnancies stained for Jag1 and CD31. Expression of Jag1 is reduced in the decidua (outlined with dashed white lines), but not the embryo of <span class="html-italic">Jag1ΔEC</span> mutants. (<b>E</b>) qRT-PCR determination of <span class="html-italic">Jag1</span> expression in implantation sites from control (<span class="html-italic">n</span> = 6) and <span class="html-italic">Jag1ΔEC</span> (<span class="html-italic">n</span> = 5) pregnancies. The relative expression level of <span class="html-italic">Jag1</span> was compared to β-actin. <span class="html-italic">Jag1</span> was significantly decreased in <span class="html-italic">Jag1ΔEC</span> mutants as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls. (<b>F</b>) Representative images of the MP of control and <span class="html-italic">Jag1ΔEC</span> implantation sites double stained for EC marker CD31 and Jag1. At the MP, expression of Jag1 in all CD31<sup>+</sup> ECs is reduced in <span class="html-italic">Jag1ΔEC</span> mutants (<span class="html-italic">n</span> = 6) as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls (<span class="html-italic">n</span> = 5). (<b>G</b>) Representative images of the MP of control and <span class="html-italic">Jag1ΔEC</span> implantation sites double stained for Jag1 and NG2. Expression of Jag1 in the ECs of the NG2<sup>+</sup> surrounded SpAs (white arrowheads) is reduced in <span class="html-italic">Jag1ΔEC</span> mutants (<span class="html-italic">n</span> = 5) as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls (<span class="html-italic">n</span> = 6). AMR= anti-mesometrial region; CTR = central region; e = embryo; MP = mesometrial pole. Scale bars = 100 μm in (<b>B</b>–<b>D</b>,<b>F</b>,<b>G</b>). Data shown as median + IQR; ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 5
<p>EC-specific loss of <span class="html-italic">Jag1</span> does not disrupt pregnancy progression or litter size at E7.5. (<b>A</b>) Number of implantation sites at E7.5 is similar between controls (<span class="html-italic">n</span> = 8) and <span class="html-italic">Jag1ΔEC</span> pregnancies (<span class="html-italic">n</span> = 7). (<b>B</b>,<b>C</b>) Representative H&E stained embryos, showing morphologic structures including the primitive streak (arrowheads), cranial neural fold (red asterisk), allantois (yellow asterisk) and somites (white arrows), observed in embryos at E7.5 (<b>B</b>) and E8.5 (<b>C</b>). (<b>D</b>) The presence of the primitive streak, allantois and cranial neural fold structures is similar in control and <span class="html-italic">Jag1ΔEC</span> pregnancies. Data were analyzed using Fisher’s exact test, comparing morphologic structures in control and <span class="html-italic">Jag1ΔEC</span> pregnancies to those expected in pregnancies at E7.5 [<a href="#B46-ijms-21-06477" class="html-bibr">46</a>].</p> "> Figure 6
<p>Expression of Notch ligand, Dll4, and Notch effectors are increased in ECs of <span class="html-italic">Jag1ΔEC</span> decidua. (<b>A</b>–<b>C</b>) Expression of Dll4 in capillaries and SpAs in <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> control and <span class="html-italic">Jag1∆EC</span> pregnancies was determined by double staining IF for Dll4 and CD31 or NG2. Representative images of the MP (<b>A</b>) and AMR (<b>B</b>) of control and <span class="html-italic">Jag1ΔEC</span> implantation sites. (<b>A</b>) Dll4 expression is increased in CD31<sup>+</sup> ECs at the MP of <span class="html-italic">Jag1ΔEC</span> mutants (<span class="html-italic">n</span> = 4) as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls (<span class="html-italic">n</span> = 5). (<b>B</b>) Dll4 expression is increased in CD31<sup>+</sup> capillary ECs in the AMR of <span class="html-italic">Jag1ΔEC</span> mutants (<span class="html-italic">n</span> = 6) as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls (<span class="html-italic">n</span> = 6). (<b>C</b>) Representative images of the MP of control and <span class="html-italic">Jag1ΔEC</span> implantation sites double stained for Dll4 and NG2. Expression of Dll4 in the ECs of the NG2<sup>+</sup> surrounded SpAs is unchanged in <span class="html-italic">Jag1ΔEC</span> mutants (<span class="html-italic">n</span> = 6) as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls (<span class="html-italic">n</span> = 6). (<b>D</b>) qRT-PCR determination of Notch effector gene expression in implantation sites from control (<span class="html-italic">n</span> = 5) and <span class="html-italic">Jag1ΔEC</span> (<span class="html-italic">n</span> = 5) pregnancies. The relative expression level of each gene was compared to β-actin. <span class="html-italic">Nrarp</span> and <span class="html-italic">Hey2</span> are significantly increased in <span class="html-italic">Jag1ΔEC</span> mutants as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls. AMR = anti-mesometrial region; MP = mesometrial pole. Scale bars = 50 μm. Data shown are median +IQR. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 7
<p>Increased Notch signaling in the anti-mesometrial decidua decreases EC proliferation and expression of VEGFR2. (<b>A</b>–<b>C</b>) High magnification images of sections double stained to detect expression of N1ICD and CD31, Dll4 or Ki67. (<b>A</b>) Expression of the N1ICD in CD31<sup>+</sup> ECs in the AMR of <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> control and <span class="html-italic">Jag1∆EC</span> pregnancies was determined by double staining IF for N1ICD and CD31. Representative images of control and <span class="html-italic">Jag1ΔEC</span> implantation sites are shown. Nuclear expression of N1ICD (white arrowheads) is increased in CD31<sup>+</sup> ECs in the AMR of <span class="html-italic">Jag1ΔEC</span> mutants (<span class="html-italic">n</span> = 5) as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls (<span class="html-italic">n</span> = 5). (<b>B</b>) N1ICD and Dll4 are expressed in adjacent cells in the AMR (white arrowheads) of <span class="html-italic">Jag1∆EC</span> pregnancies. (<b>C</b>) EC proliferation in the AMR of <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> control and <span class="html-italic">Jag1∆EC</span> pregnancies was determined by double staining IF for EC proliferation marker, Ki67 and CD31. Representative images of control and <span class="html-italic">Jag1ΔEC</span> implantation sites are shown. Ki67 expression (white arrowheads) is decreased in CD31<sup>+</sup> ECs in the AMR of <span class="html-italic">Jag1ΔEC</span> mutants (<span class="html-italic">n</span> = 5) as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls (<span class="html-italic">n</span> = 5). (<b>D</b>) Expression of VEGFR2 with respect to CD31<sup>+</sup> ECs in the AMR was determined by comparison of expression of VEGFR2 and CD31 in adjacent sections, in like-regions, of implantation sites from <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> control and <span class="html-italic">Jag1∆EC</span> pregnancies. Representative images of the AMR highlighting areas (decidua within dashed red lines) used to measure signal density from control and <span class="html-italic">Jag1ΔEC</span> implantation sites are shown (i–iv). VEGFR2 expression is decreased in CD31<sup>+</sup> capillary ECs in the anti-mesometrial decidua of <span class="html-italic">Jag1ΔEC</span> mutants (<span class="html-italic">n</span> = 5) as compared to <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> controls (<span class="html-italic">n</span> = 5). Insets highlight VEGFR2 expression in decidual vessels. Black arrowheads highlight VEGFR2 expression in the myometrial vessels, which is similar in <span class="html-italic">Jag1ΔEC</span> mutants and controls. AMR = anti-mesometrial region; N1ICD = Notch1 intracellular domain. Scale bars = 50 μm. Data shown as median + IQR; * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 8
<p>EC-specific loss of <span class="html-italic">Jag1</span> does not impact the frequency of CD31<sup>+</sup> ECs in implantation sites. (<b>A</b>) Representative dot plot of flow cytometry (FCM) data showing gating strategy to identify CD31<sup>+</sup> CD45<sup>–</sup> EC populations in implantation sites from wild-type C57BL/6 mice at E7.5. (<b>B</b>) Results of FCM analysis to assess CD31<sup>+</sup>CD45<sup>−</sup> cell populations in uteri from nonpregnant C57BL/6 mice, and in the myometrium and implantation sites from pregnant C57BL/6 mice at E7.5. The percentage of CD31<sup>+</sup>CD45<sup>−</sup> ECs is significantly higher in implantation sites compared to the myometrium or nonpregnant uteri. (<b>C</b>) Results of FCM analysis to determine the percentage of CD31<sup>+</sup>CD45<sup>−</sup> ECs in the myometrium and implantation sites of <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> control and <span class="html-italic">Jag1ΔEC</span> pregnancies at E7.5. The percentage of CD31<sup>+</sup>CD45<sup>−</sup> ECs in the myometrium and implantation sites of <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> control and <span class="html-italic">Jag1ΔEC</span> pregnancies is similar. IS = implantation site; myo = myometrium; NP = nonpregnant; each group contains <span class="html-italic">n</span> = 3–5 individual mice. Data shown as median + IQR; * <span class="html-italic">p</span> < 0.05.</p> "> Figure 9
<p>EC-specific loss of <span class="html-italic">Jag1</span> does not impact endothelial and mural cell density. (<b>A</b>–<b>C</b>) Expression of CD31<sup>+</sup> was quantified to determine blood vessel density in each region of the implantation site. (<b>A</b>) Density of CD31<sup>+</sup> ECs was similar in <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> control and <span class="html-italic">Jag1ΔEC</span> pregnancies in the MP (A) and CTR (<b>B</b>) of the MR and in the AMR (<b>C</b>). (<b>D</b>–<b>F</b>) Implantation sites stained for mural markers, NG2, PDGFRβ or SMA are assessed for mural cell content at the MP. Expression of NG2 (<b>D</b>), PDGFRβ (<b>E</b>) and SMA (<b>F</b>) is similar in <span class="html-italic">Cdh5-Cre<sup>ERT2</sup></span> control and <span class="html-italic">Jag1</span><span class="html-italic">ΔEC</span> pregnancies in the MP. AMR = anti-mesometrial region; CTR = central region; MP = mesometrial pole; MR = mesometrial region. Data shown as median + IQR.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Characterization of Vasculature in the Mouse Implantation Site at E7.5
2.2. Characterization of Notch Expression in the Decidual Vasculature
2.3. EC-Specific Deletion of Jag1 in Early Pregnancy
2.4. Loss of Endothelial Jag1 Does Not Impact Pregnancy at E7.5
2.5. Expression of Notch Ligand, Dll4, and Notch Effectors Is Increased in Jag1∆EC Pregnancies at E7.5
2.6. Jag1/Notch Signaling Regulates Angiogenic Gene Expression and Endothelial Proliferation in the Anti-Mesometrial Decidua
2.7. EC-Specific Loss of Jag1 Does Not Impact CD31+ EC Content in Pregnant Uteri at E7.5
2.8. Vasculature Is Similar in Implantation Sites of Control and Jag1ΔEC Pregnancies
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Quantitative Reverse Transcription-PCR
4.3. Analysis of Embryo Morphology
4.4. Immunofluorescence and Immunohistochemistry
4.5. Flow Cytometry
4.6. Imaging
4.7. Morphometric Analyses
4.8. Statistics
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Marchetto, N.M.; Begum, S.; Wu, T.; O’Besso, V.; Yarborough, C.C.; Valero-Pacheco, N.; Beaulieu, A.M.; Kitajewski, J.K.; Shawber, C.J.; Douglas, N.C. Endothelial Jagged1 Antagonizes Dll4/Notch Signaling in Decidual Angiogenesis during Early Mouse Pregnancy. Int. J. Mol. Sci. 2020, 21, 6477. https://doi.org/10.3390/ijms21186477
Marchetto NM, Begum S, Wu T, O’Besso V, Yarborough CC, Valero-Pacheco N, Beaulieu AM, Kitajewski JK, Shawber CJ, Douglas NC. Endothelial Jagged1 Antagonizes Dll4/Notch Signaling in Decidual Angiogenesis during Early Mouse Pregnancy. International Journal of Molecular Sciences. 2020; 21(18):6477. https://doi.org/10.3390/ijms21186477
Chicago/Turabian StyleMarchetto, Nicole M., Salma Begum, Tracy Wu, Valerie O’Besso, Christina C. Yarborough, Nuriban Valero-Pacheco, Aimee M. Beaulieu, Jan K. Kitajewski, Carrie J. Shawber, and Nataki C. Douglas. 2020. "Endothelial Jagged1 Antagonizes Dll4/Notch Signaling in Decidual Angiogenesis during Early Mouse Pregnancy" International Journal of Molecular Sciences 21, no. 18: 6477. https://doi.org/10.3390/ijms21186477