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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/H1326    most recent 00900.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Uzarski, J. Articles by Goldman, J. Search for Related Content PubMed PubMed Citation Articles by Uzarski, J. Articles by Goldman, J.

The resolution of lymphedema by interstitial flow in the mouse tail skin

¹Biomedical Engineering Department, Michigan Technological University, Houghton, Michigan; and ²ImClone Systems, New York, New York

Submitted 2 August 2007 ; accepted in final form 14 January 2008

Lymphangiogenesis is considered a promising approach for increasing fluid drainage during secondary lymphedema. However, organization of lymphatics into functional capillaries may be dependent upon interstitial flow (IF). The present study was undertaken to determine the importance of lymphangiogenesis for lymphedema resolution. We created a lymphatic obstruction that produces lymphedema in mouse tail skin. The relatively scar-free skin regeneration that occurred across the obstruction allowed the progression of lymphangiogenesis to be observed and compared with the evolution of lymphedema. The role of vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3 signaling in lymphedema resolution was investigated by exogenous administration of VEGF-C or neutralizing antibodies against VEGFR-3. VEGF-C protein improved lymphedema at 15 days [reducing dermal thickness from 742 ± 105 to 559 ± 141 µm with 95% confidence intervals (CIs), P < 0.05] without increasing lymphatic capillary coverage (11.6 ± 6.4% following VEGF-C treatment relative to 9.6 ± 6.2% with 95% CIs, P > 0.50). Blocking VEGFR-3 signaling did not inhibit lymphedema resolution at 25 days (dermal thickness of 462 ± 127 µm following VEGFR-3 inhibition relative to 502 ± 87 µm with 95% CIs) or inhibit IF, although VEGFR-3 blocking prevented lymphangiogenesis (reducing lymphatic coverage to 0.2 ± 0.7% relative to 8.7 ± 7.3% with 95% CIs, P < 0.005). A second mouse tail lymphedema model was employed to investigate the ability of VEGF-C to increase fluid drainage across a scar. We found that neither neutralization of VEGFR-3 nor administration of VEGF-C affected the course of skin swelling over 25 days. These findings suggest that resolution of lymphedema in the mouse tail skin may be more dependent upon IF and regeneration of the extracellular matrix across the obstruction than lymphatic capillary regeneration.

lymphatic capillary; lymphangiogenesis; vascular endothelial growth factor-C; vascular endothelial growth factor receptor 3; skin; extracellular matrix