Remodeling of the lymphatic vasculature during mouse mammary gland morphogenesis is mediated via epithelial-derived lymphangiogenic stimuli

Kelly L. Betterman, Sophie Paquet-Fifield, Marie-Liesse Labat, Jane E. Visvader, Lisa M. Butler, Steven A. Stacker, Marc G. Achen, Natasha L. Harvey

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2225-2238
Number of pages14
JournalAmerican Journal of Pathology
Volume181
Issue number6
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

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Human Mammary Glands
Morphogenesis
Lymphatic Vessels
Vascular Endothelial Growth Factor D
Lymphangiogenesis
Vascular Endothelial Growth Factor C
Blood Vessels
Endothelial Cells
Vascular Endothelial Growth Factor Receptor-3
Progesterone Receptors
Conditioned Culture Medium
Estrogen Receptors
Breast
Homeostasis
Epithelial Cells
Steroids
Hormones
Growth

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Remodeling of the lymphatic vasculature during mouse mammary gland morphogenesis is mediated via epithelial-derived lymphangiogenic stimuli. / Betterman, Kelly L.; Paquet-Fifield, Sophie; Labat, Marie-Liesse; Visvader, Jane E.; Butler, Lisa M.; Stacker, Steven A.; Achen, Marc G.; Harvey, Natasha L.

In: American Journal of Pathology, Vol. 181, No. 6, 01.12.2012, p. 2225-2238.

Research output: Contribution to journalArticle

Betterman, Kelly L. ; Paquet-Fifield, Sophie ; Labat, Marie-Liesse ; Visvader, Jane E. ; Butler, Lisa M. ; Stacker, Steven A. ; Achen, Marc G. ; Harvey, Natasha L. / Remodeling of the lymphatic vasculature during mouse mammary gland morphogenesis is mediated via epithelial-derived lymphangiogenic stimuli. In: American Journal of Pathology. 2012 ; Vol. 181, No. 6. pp. 2225-2238.
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