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Roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangioge

PostPosted: Sat Feb 03, 2007 4:42 pm
by patoco
Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis.

Goldman J, Rutkowski JM, Shields JD, Pasquier MC, Cui Y, Schmokel HG,
Willey S, Hicklin DJ, Pytowski B, Swartz MA.
*Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne,
Lausanne, Switzerland;Tumor Biology ImClone Systems, New York, New
York, USA; andExperimental Therapeutics, ImClone Systems, New York, New York, USA.

Activation of vascular endothelial growth factor (VEGF) receptor-3
(VEGFR-3) by VEGF-C initiates lymphangiogenesis by promoting lymphatic proliferation and migration. However, it is unclear whether VEGFR-3 signaling is required beyond these initial stages, namely during the organization of new lymphatic endothelial cells (LECs) into functional
capillaries. Furthermore, the role of VEGFR-2, which is also expressed
on LECs and binds VEGF-C, is unclear. We addressed these questions by
selectively neutralizing VEGFR-3 and/or VEGFR-2 for various time
periods in an adult model of lymphangiogenesis in regenerating skin.
While blocking either VEGFR-2 or VEGFR-3 with specific antagonist mAbs
(DC101 and mF4-31C1, respectively) prior to lymphatic migration
prevented lymphangiogenesis, blocking VEGFR-3 subsequent to migration
did not affect organization into functional capillaries, and VEGFR-2
blocking had only a small hindrance on organization. These findings
were confirmed in vitro using human LECs and anti-human antagonist mAbs (IMC-1121a and hF4-3C5): both VEGFR-2 and -3 signaling were required for migration and proliferation, but tubulogenesis in 3D cultures was unaffected by VEGFR-3 blocking and partially hindered by VEGFR-2

Furthermore, both in vitro and in vivo, while VEGFR-3
blocking had no effect on LEC organization, coneutralization of
VEGFR-2, and VEGFR-3 completely prevented lymphatic organization. Our
findings demonstrate that cooperative signaling of VEGFR-2 and -3 is
necessary for lymphatic migration and proliferation, but VEGFR-3 is
redundant with VEGFR-2 for LEC organization into functional

Goldman, J., Rutkowski, J. M., Shields, J. D., Pasquier,
M. C., Cui, Y., Schmokel, H. G., Willey, S., Hicklin, D. J., Pytowski,
B., Swartz, M. A. Cooperative and redundant roles of VEGFR-2 and
VEGFR-3 signaling in adult lymphangiogenesis.

PMID: 17210781 [PubMed - as supplied by publisher] ... etrieve&...


Pat O'Connor
Lymphedema People