Abstract
Background
The lymphatic vascular system regulates tissue fluid homeostasis and plays important
roles in immune surveillance, inflammation and cancer metastasis. However, the molecular
mechanisms involved in the regulation of lymphangiogenesis remain incompletely characterized.
Objective
We aimed to identify new pathways involved in the promotion of skin lymphangiogenesis.
Methods
We used a mouse embryonic stem cell-derived embryoid body vascular differentiation
assay to investigate the effects of a selection of pharmacological agents with the
potential to inhibit blood and/or lymphatic vessel formation. We also used a subcutaneous
Matrigel assay to study candidate lymphangiogenesis factors as well as skin-specific
transgenic mice.
Results
We found that compounds inhibiting the epidermal growth factor (EGF) receptor (EGFR)
led to an impaired formation of lymphatic vessel-like structures. In vitro studies with human dermal lymphatic endothelial cells (LECs), that were found to
express EGFR, revealed that EGF promotes lymphatic vessel formation. This effect was
inhibited by EGFR-blocking antibodies and by low molecular weight inhibitors of the
EGFR associated tyrosine kinase. Incorporation of EGF into a mouse matrigel plug assay
showed that EGF promotes enlargement of lymphatic vessels in the skin in vivo. Moreover, transgenic mice with skin-specific overexpression of amphiregulin, another
agonistic ligand of the EGFR, displayed an enhanced size and density of lymphatic
vessels in the skin.
Conclusion
These findings reveal that EGFR activation is involved in lymphatic remodeling and
suggest that specific EGFR antagonists might be used to inhibit pathological lymphangiogenesis.
Keywords
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Article info
Publication history
Published online: May 24, 2013
Accepted:
April 23,
2013
Received in revised form:
April 21,
2013
Received:
August 28,
2012
Identification
Copyright
© 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Inc. All rights reserved.
