Therapeutic responses to exogenous VEGF-C administration in experimental lymphedema: immunohistochemical and molecular characterization.

[lymphedemapeople]

Therapeutic responses to exogenous VEGF-C administration in
experimental lymphedema: immunohistochemical and molecular
characterization.

Lymphat Res Biol. 2009;

Jin da P, An A, Liu J, Nakamura K, Rockson SG.
Lymphatic Research and Medicine, Stanford University School of
Medicine, Falk Cardiovascular Research Cente, Stanford, California
94305, USA.

BACKGROUND: In a widely employed murine tail model of human acquired
lymphedema, we have previously observed that, distal to the site of
experimental lymphatic ablation, there is immunohistochemical evidence
of a profound increase in cutaneous lymphatic vessel number and size
that normalizes after VEGF-C administration.

OBJECTIVE: In order to investigate the mechanistic basis of the
lymphatic microvascular remodeling, we have studied the lymphedematous
responses to VEGF-C after co-administration of systemic VEGFR-3
neutralizing antibody. We have also undertaken genome-wide whole-
tissue transcriptional profiling of lymphedematous tissues before and
after exogenous VEGF-C administration. STUDY

DESIGN: We provoked postsurgical lymphedema in the mouse tail model
and assessed the effects of exogenously administered human recombinant
VEGF-C in the presence of a monoclonal anti-VEGFR-3 antibody.
Polyclonal IgG was administered to a series of control subjects.
Microvascular lymphatic remodeling was assessed through quantitative
and qualitative anti-LYVE1 immunohistochemistry. Genome-wide
transcriptional profiling was performed in whole skin derived from
lymphedema with and without exogenous VEGF-C administration. Normal
mice and surgical shams served as controls.

RESULTS: In the presence of the monoclonal anti-VEGFR-3 neutralizing
antibody, positive lymphatic microvascular remodeling in
lymphedematous skin is nearly completely abrogated. Furthermore, the
therapeutic impact of added VEGF-C is markedly attenuated, as is the
ability of the growth factor to ameliorate tissue edema.
Transcriptional profiling of the VEGF-C responses in treated
lymphedema reveals a very restricted list of genes whose expression is
upregulated in lymphedema and re-normalized following VEGF-C
treatment.

CONCLUSION: The postsurgical murine tail model of lymphedema closely
simulates attributes of human lymphedema. The current series of
investigations underscores the utility of the murine tail model to the
preclinical and translational investigation of lymphedema. The derived
insights continue to focus favorably upon the central role of the
VEGFR-3 receptor and its ligands in the development and therapeutic
resolution of lymphedema. Whole tissue transcriptional profiling
continues to shed light on disease mechanisms and potential future
targets for therapeutic intervention.

Mary Ann Liebert Publications

http://www.liebertonline.com/doi/abs/10.1089/lrb.2009.0002