Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation
Kristy Red-Horse, Jose Rivera, Andrea Schanz, Yan Zhou, Virginia Winn, Mirhan Kapidzic, Emin Maltepe, Kelly Okazaki, Ronit Kochman, Kim Chi Vo, Linda Giudice, Adrian Erlebacher, Joseph M. McCune, Cheryl A. Stoddart, Susan J. Fisher
Kristy Red-Horse, Jose Rivera, Andrea Schanz, Yan Zhou, Virginia Winn, Mirhan Kapidzic, Emin Maltepe, Kelly Okazaki, Ronit Kochman, Kim Chi Vo, Linda Giudice, Adrian Erlebacher, Joseph M. McCune, Cheryl A. Stoddart, Susan J. Fisher
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Research Article Angiogenesis

Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation

Abstract

We studied the vascular effects of invasive human cytotrophoblasts in vivo by transplanting placental villi to the fifth mammary fat pads or beneath the kidney capsules of Scid mice. Over 3 weeks, robust cytotrophoblast invasion was observed in both locations. The architecture of the mammary fat pad allowed for detailed analysis of the cells’ interactions with resident murine blood vessels, which revealed specific induction of apoptosis in the endothelial cells and smooth muscle walls of the arterioles. This finding, and confirmation of the results in an in vitro coculture model, suggests that a parallel process is important for enabling cytotrophoblast endovascular invasion during human pregnancy. Cytotrophoblast invasion of the kidney parenchyma was accompanied by a robust lymphangiogenic response, while in vitro, the cells stimulated lymphatic endothelial cell migration via the actions of VEGF family members, FGF, and TNF-α. Immunolocalization analyses revealed that human pregnancy is associated with lymphangiogenesis in the decidua since lymphatic vessels were not a prominent feature of the nonpregnant endometrium. Thus, the placenta triggers the development of a decidual lymphatic circulation, which we theorize plays an important role in maintaining fluid balance during pregnancy, with possible implications for maternal-fetal immune cell trafficking.

Authors

Kristy Red-Horse, Jose Rivera, Andrea Schanz, Yan Zhou, Virginia Winn, Mirhan Kapidzic, Emin Maltepe, Kelly Okazaki, Ronit Kochman, Kim Chi Vo, Linda Giudice, Adrian Erlebacher, Joseph M. McCune, Cheryl A. Stoddart, Susan J. Fisher

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Figure 6

Human cytotrophoblasts induce lymphatic endothelial cell infiltration.

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Human cytotrophoblasts induce lymphatic endothelial cell infiltration. (...
(A–D) Double staining of histological sections of human placental implants. Cytotrophoblasts were visualized by cytokeratin 7 staining, and lymphatic endothelial cells were labeled with LYVE-1. Merged images include DAPI staining (blue). (A) At 1 week after implantation, preexisting LYVE-1–positive vessels were detected beyond the front of cytotrophoblast invasion. Insets show higher-magnification views of the boxed areas. Anti–LYVE-1 also stained CD45-positive macrophages within the kidney capsule (arrowheads in A, C, and D). (B) LYVE-1 (red) and DAPI (blue) staining in control kidneys. (C) After 2 weeks, cells that stained for LYVE-1 began to infiltrate the implants (arrows). (D) By 3 weeks, infiltration had increased (arrows). (E–G) In contrast, mouse trophoblast implants (dotted line, E) did not contain LYVE-1–positive cells (F). (G) Nuclei were labeled with DAPI. (H–J) Immunohistochemistry of adjacent sections showed that within the renal parenchyma, which the cytotrophoblasts invaded (H), LYVE-1 expression did not colocalize with CD45 staining (arrows, I and J). Tissue macrophages within the capsule that stained for CD45 also reacted with LYVE-1 (arrowheads, I and J). Scale bars: 500 μm (A–G); 20 μm (A, insets); 50 μm (H–J).