T1{alpha}/PODOPLANIN IS ESSENTIAL FOR CAPILLARY MORPHOGENESIS IN LYMPHATIC ENDOTHELIAL CELLS.

[lymphedemapeople]

T1{alpha}/PODOPLANIN IS ESSENTIAL FOR CAPILLARY MORPHOGENESIS IN
LYMPHATIC ENDOTHELIAL CELLS.

Am J Physiol Lung Cell Mol Physiol. 2008 Jul 25

Navarro A, Perez RE, Rezaiekhaligh M, Mabry SM, Ekekezie II.
Children's Mercy Hospitals and Clinics/University of Missouri - Kansas
City School of Medicine, Kansas City, Missouri.

The lymphatic vasculature functions to maintain tissue perfusion
homeostasis. Defects in its formation or disruption of the vessels
result in lymphedema, the effective treatment of which is hampered by
limited understanding of factors regulating lymph vessel formation.
Mice lacking T1alpha/podoplanin, a lymphatic endothelial cell trans-
membrane protein, have malformed lymphatic vasculature with lymphedema
at birth, but the molecular mechanism for this phenotype is unknown.
Here we show, using primary human lung microvascular lymphatic
endothelial cells (HMVEC-LLy), that small interfering RNA (siRNA)
mediated silence of podoplanin gene expression has the dramatic effect
of blocking capillary tube formation in Matrigel(TM). In addition,
localization of phosphorylated ezrin/radixin/moesin (ERM) proteins to
plasma membrane extensions, an early event in the capillary
morphogenic program in lymphatic endothelial cells, is impaired. We
find that cells with decreased podoplanin expression fail to properly
activate the small GTPase RhoA early (by 30 minutes) after plating on
Matrigel(TM), and Rac1 shows a delay in its activation. Further
indication podoplanin action is linked to RhoA activation is that use
of a cell permeable inhibitor of RhoA inhibited lymphatic endothelial
capillary tube formation in the same manner as did podoplanin gene
silencing, which was not mimicked by treatment with a Rac1 inhibitor.
These data clearly demonstrate that early activation of RhoA in the
lymphangiogenic process, which is required for the successful
establishment of the capillary network, is dependent on podoplanin
expression. To our knowledge, this is the first time that a mechanism
has been suggested to explain the role of podoplanin in
lymphangiogenesis. Key words: Lymphedema, lymphatics, GTPases, RhoA,
Rac1, Matrigel(TM).

http://ajplung.physiology.org/cgi/content/abstract/90262.2008v1

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Pat O'Connor
Lymphedema People
http://www.lymphedemapeople.com