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

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

Postby patoco » Sat Feb 03, 2007 4:42 pm

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
blocking.

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
capillaries.--

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]


http://www.ncbi.nlm.nih.gov/entrez/quer ... etrieve&...

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