VEGF and VEGFR-2 (KDR) internalization is required for endothelial recovery during wound healing
- Angiogenesis Laboratory, Centro de Investigacao em Patobiologia Molecular (CIPM), Instituto Portugues de Oncologia Francisco Gentil (IPOFG)-CROL, SA, Lisbon (Portugal)
- Instituto de Biopatologia Quimica, Faculdade de Medicina de Lisboa/Unidade de Biopatologia Vascular, Instituto de Medicina Molecular, Lisbon (Portugal)
- ImClone Systems, New York (United States)
- Angiogenesis Laboratory, Centro de Investigacao em Patobiologia Molecular (CIPM), Instituto Portugues de Oncologia Francisco Gentil (IPOFG)-CROL, SA, Lisbon (Portugal) and Instituto Gulbenkian de Ciencia (IGC), Oeiras (Portugal) and Instituto de Medicina Molecular, Lisbon (Portugal)
Vascular endothelial growth factor (VEGF) receptor activation regulates endothelial cell (EC) survival, migration and proliferation. Recently, it was suggested the cross-talk between the VEGF receptors-1 (FLT-1) and -2 (KDR) modulated several of these functions, but the detailed molecular basis for such interactions remained unexplained. Here we demonstrate for the first time that VEGF stimulation of EC monolayers induced a rapid FLT-1-mediated internalization of KDR to the nucleus, via microtubules and the endocytic pathway, internalization which required the activation of PI 3-kinase/AKT. KDR deletion mutants were generated in several tyrosine residues; in these, VEGF-induced KDR internalization was impaired, demonstrating this process required activation (phosphorylation) of the receptor. Furthermore, we demonstrate that in vitro wounding of EC monolayers leads to a rapid and transient internalization of VEGF + KDR to the nucleus, which is essential for monolayer recovery. Notably, FLT-1 blockade impedes VEGF and KDR activation and internalization, blocking endothelial monolayer recovery. Our data reveal a previously unrecognized mechanism induced by VEGF on EC, which regulates EC recovery following wounding, and as such indicate novel targets for therapeutic intervention.
- OSTI ID:
- 20972144
- Journal Information:
- Experimental Cell Research, Vol. 313, Issue 8; Other Information: DOI: 10.1016/j.yexcr.2007.02.020; PII: S0014-4827(07)00056-0; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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