Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation
Kristy Red-Horse, … , Cheryl A. Stoddart, Susan J. Fisher
Kristy Red-Horse, … , Cheryl A. Stoddart, Susan J. Fisher
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2643-2652. https://doi.org/10.1172/JCI27306.
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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 1

Human cytotrophoblasts induce arterial apoptosis during vascular remodeling in vivo.

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Human cytotrophoblasts induce arterial apoptosis during vascular remodel...
Implants (first trimester human placental villi in Scid mouse mammary fat pads) were excised by dissection after 3 weeks and examined histologically. (A and B) Cytokeratin 7–positive cytotrophoblasts invaded murine stromal tissue, where they interacted with arteries (a) and veins (v). CD31 stain indicates endothelial cells. Arrow denotes apparent colocalization (yellow) within the vein wall. Nuclei were stained with DAPI. CK, cytokeratin. (C) Invading cytotrophoblasts displaced murine endothelial cells (arrow) and extended their cellular processes along the basal lamina (arrowhead). (D) α-SMA distribution in adjacent sections identified arteries, which had thicker tunica media than did veins. (E) Cytotrophoblast invasion disrupted arterial integrity and resulted in platelet deposition, visualized by staining for CD41. (G and H) TUNEL labeling revealed that cytotrophoblasts induced apoptosis of arterial smooth muscle and endothelial cells (arrowheads) but did not affect veins. (F and I) Staining TUNEL-labeled tissue sections for α-SMA (F) or CD31 (I) revealed that both cell types underwent apoptosis. (I) High-magnification image of a dying endothelial cell. (J and K) Cytotrophoblasts induced UtMVEC apoptosis in vitro. (J) After coculture with cytokeratin-positive cytotrophoblasts, approximately half the cytokeratin-negative UtMVECs that remained attached to the culture substrate were TUNEL labeled. (K) Coculture also increased the number of UtMVECs that underwent apoptosis and detached. CTB, cytotrophoblasts. Values are mean ± SEM from multiple experiments. *P < 0.01. Scale bars: 50 μm (A, D, and G); 40 μm (B, E, and H); 10 μm (C, F, I, and J).