Transmural Flow Modulates Cell and Fluid Transport Functions of Lymphatic Endothelium.
lymphedemapeople
Lymphatic Endothelium.
Circ Res. 2010 Feb 4.
Dimana O. Miteva ; Joseph M. Rutkowski ; J. Brandon Dixon ; Witold
Kilarski ; Jacqueline D. Shields ; and Melody A. Swartz *
From the Institute of Bioengineering, École Polytechnique Fédérale de
Lausanne, Switzerland.
* To whom correspondence should be addressed. E-mail:
Melody...@epfl.ch.
Key words: CCL21 • ICAM-1 • inflammation • lymphedema • in vitro •
overhydration
Rationale:
Lymphatic transport of peripheral interstitial fluid and dendritic
cells (DCs) is important for both adaptive immunity and maintenance of
tolerance to self-antigens. Lymphatic drainage can change rapidly and
dramatically on tissue injury or inflammation, and therefore increased
fluid flow may serve as an important early cue for inflammation;
however, the effects of transmural flow on lymphatic function are
unknown.
Objective:
Here we tested the hypothesis that lymph drainage regulates the fluid
and cell transport functions of lymphatic endothelium.
Methods and Results:
Using in vitro and in vivo models, we demonstrated that lymphatic
endothelium is sensitive to low levels of transmural flow. Basal-to-
luminal flow (0.1 and 1 mum/sec) increased lymphatic permeability,
dextran transport, and aquaporin-2 expression, as well as DC
transmigration into lymphatics. The latter was associated with
increased lymphatic expression of the DC homing chemokine CCL21 and
the adhesion molecules intercellular adhesion molecule-1 and
endothelial selectin. In addition, transmural flow induced
delocalization and downregulation of vascular endothelial cadherin and
PECAM-1 (platelet/endothelial cell adhesion molecule-1). Flow-enhanced
DC transmigration could be reversed by blocking CCR7, intercellular
adhesion molecule-1, or endothelial selectin. In an experimental model
of lymphedema, where lymphatic drainage is greatly reduced or absent,
lymphatic endothelial expression of CCL21 was nearly absent.
Conclusions:
These findings introduce transmural flow as an important regulator of
lymphatic endothelial function and suggest that flow might serve as an
early inflammatory signal for lymphatics, causing them to regulate
transport functions to facilitate the delivery of soluble antigens and
DCs to lymph nodes.
http://circres.ahajournals.org/cgi/content/abstract/CIRCRESAHA.109.207274v1