In vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis

Abstract

Lymphatic vessel growth or lymphangiogenesis occurs during embryonic development and wound healing and plays an important role in tumor metastasis and inflammatory diseases. However, the possibility of noninvasive detection and quantification of lymphangiogenesis has been lacking. Here, we present the Vegfr3 EGFPLuc mouse model, where an EGFP-luciferase fusion protein, expressed under the endogenous transcriptional control of the Vegfr3 gene, allows the monitoring of physiological and pathological lymphangiogenesis in vivo. We show tracking of lymphatic vessel development during embryogenesis as well as lymphangiogenesis induced by specific growth factors, during wound healing and in contact hypersensitivity (CHS) -induced inflammation where we also monitor down-regulation of lymphangiogenesis by the glucocorticoid dexamethasone. Importantly, the Vegfr3-reporter allowed us to tracking tumor-induced lymphangiogenesis at the tumor periphery and in lymph nodes in association with the metastatic process. This is the first reporter mouse model for luminescence imaging of lymphangiogenesis. It should provide an important tool for studying the involvement of lymphangiogenesis in pathological processes.bioluminescence | fluorescence | knockin mouse

Lymphatic vessels and tertiary lymphoid organs

“…Analysis of lymphocyte, DC, and antigen-trafficking patterns in TLOs in real time in vivo is now possible with the use of mice that express fluorescent markers for HEVs (80) and LVs (79,81). Although the technique of in vivo imaging is well established for analysis of trafficking in LNs (82), addressing this issue in TLOs is a greater challenge.…”

Lymphangiogenic factors, mechanisms, and applications

“…Lymphangiogenic signaling is highly active during development and decreases to very low levels in adulthood; however, these pathways can be re-activated in pathological conditions (90). Aberrant growth or activation of lymphatic vessels is associated with cancer and some chronic inflammatory diseases (91).…”

CCBE1 Enhances Lymphangiogenesis via A Disintegrin and Metalloprotease With Thrombospondin Motifs-3–Mediated Vascular Endothelial Growth Factor-C Activation

“…The detection of luciferase activity in EGFP/Luc Vegfr3 EGFP/Luc mice was performed as described previously. 19 The National Board for Animal Experiments of the Provincial State Office of Southern Finland approved all of the animal experiments carried out in this study.…”