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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/H2176    most recent 01011.2006v2 01011.2006v1 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 HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Goldman, J. Articles by Ongstad, E. L. Search for Related Content PubMed PubMed Citation Articles by Goldman, J. Articles by Ongstad, E. L.

Regulation of lymphatic capillary regeneration by interstitial flow in skin

¹Biomedical Engineering Department and ⁴Material Science and Engineering, Michigan Technological University, Houghton, Michigan; ²Molecular and Cellular Biology, ImClone Systems, New York, New York; and ³Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Submitted 22 September 2006 ; accepted in final form 18 December 2006

Decreased interstitial flow (IF) in secondary lymphedema is coincident with poor physiological lymphatic regeneration. However, both the existence and direction of causality between IF and lymphangiogenesis remain unclear. This is primarily because the role of IF and its importance relative to the action of the prolymphangiogenic growth factor vascular endothelial growth factor (VEGF)-C (which signals primarily through its receptor VEGFR-3) are poorly understood. To clarify this, we explored the cooperative roles of VEGFR-3 and IF in a mouse model of lymphangiogenesis in regenerating skin. Specifically, a region of lymphangiogenesis was created by substituting a portion of mouse tail skin with a collagen gel within which lymphatic capillaries completely regenerate over a period of 60 days. The relative importance of IF and VEGF-C signaling were evaluated by either inhibiting VEGFR-3 signaling with antagonistic antibodies or by reducing IF. In some cases, VEGF-C signaling was then increased with exogenous protein. To clarify the role of IF, the distribution of endogenous matrix metalloproteinases (MMPs) and VEGF-C within the regenerating region was determined. It was found that inhibition of either VEGFR-3 or IF suppressed endogenous lymphangiogenesis. Reduction of IF was found to decrease lymphatic migration and transport of endogenous MMP and VEGF-C through the regenerating region. Therapeutic VEGF-C administration restored lymphangiogenesis following inhibition of VEGFR-3 but did not increase lymphangiogenesis following inhibition of IF. These results identify IF as an important regulator of the pro-lymphangiogenic action of VEGF-C.

vascular endothelial growth factor receptor-3; endothelial cell

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