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Type: Journal article
Title: Remodeling of the lymphatic vasculature during mouse mammary gland morphogenesis is mediated via epithelial-derived lymphangiogenic stimuli
Author: Betterman, K.
Paquet- Fifield, S.
Asselin-Labat, M.
Visvader, J.
Butler, L.
Stacker, S.
Achen, M.
Harvey, N.
Citation: American Journal of Pathology, 2012; 181(6):2225-2238
Publisher: Amer Soc Investigative Pathology Inc
Issue Date: 2012
ISSN: 0002-9440
Statement of
Kelly L. Betterman, Sophie Paquet-Fifield, Marie-Liesse Asselin-Labat, Jane E. Visvader, Lisa M. Butler, Steven A. Stacker, Marc G. Achen, and Natasha L. Harvey
Abstract: Despite the key roles of lymphatic vessels in homeostasis and disease, the cellular sources of signals that direct lymphatic vascular growth and patterning remain unknown. Using high-resolution imaging in two and three dimensions, we demonstrated that postnatal mouse mammary gland lymphatic vessels share an intimate spatial association with epithelial ducts and large blood vessels. We further demonstrated that the lymphatic vasculature is remodeled together with the mammary epithelial tree and blood vasculature during postnatal mouse mammary gland morphogenesis. Neither estrogen receptor α nor progesterone receptor were detected in lymphatic endothelial cells in the mouse mammary gland, suggesting that mammary gland lymphangiogenesis is not likely regulated directly by these steroid hormones. Epithelial cells, especially myoepithelial cells, were determined to be a rich source of prolymphangiogenic stimuli including VEGF-C and VEGF-D with temporally regulated expression levels during mammary gland morphogenesis. Blockade of VEGFR-3 signaling using a small-molecule inhibitor inhibited the proliferation of primary lymphatic endothelial cells promoted by mammary gland conditioned medium, suggesting that lymphangiogenesis in the mammary gland is likely driven by myoepithelial-derived VEGF-C and/or VEGF-D. These findings provide new insight into the architecture of the lymphatic vasculature in the mouse mammary gland and, by uncovering the proximity of lymphatic vessels to the epithelial tree, suggest a potential mechanism by which metastatic tumor cells access the lymphatic vasculature.
Keywords: Blood Vessels; Epithelium; Mammary Glands, Animal; Endothelial Cells; Lymphatic Vessels; Animals; Mice, Inbred C57BL; Animals, Newborn; Mice; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factor D; Estrogen Receptor alpha; Receptors, Progesterone; RNA, Messenger; Cell Proliferation; Gene Expression Regulation, Developmental; Lymphangiogenesis; Time Factors; Female
Rights: Copyright © 2012 American Society for Investigative Pathology
RMID: 0020123166
DOI: 10.1016/j.ajpath.2012.08.035
Appears in Collections:Medicine publications

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