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* Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;
Tumor Biology ImClone Systems, New York, New York, USA; and
Experimental Therapeutics, ImClone Systems, New York, New York, USA
2Correspondence: Institute of Bioengineering, School of Life Sciences, LMBM, Station 15, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. E-mail: melody.swartz{at}epfl.ch
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., Schmökel, 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.
Key Words: VEGF-C • mouse • in vitro wound healing • vasculogenesis
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